1950a Psychopharmacology Part 2 of 2

Slide 1 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO

Slide 2 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO

Slide 3 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950?

Slide 4 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950?

Slide 5 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950

Slide 6 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford

Slide 7 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford

Slide 8 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950

Slide 9 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950?

Slide 10 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950?

Slide 11 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter.

Slide 12 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950?

Slide 13 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST

Slide 14 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums.

Slide 15 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods

Slide 16 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy

Slide 17 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods

Slide 18 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy

Slide 19 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW…

Slide 20 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES

Slide 21 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines…

Slide 22 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines…

Slide 23 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of)

Slide 24 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE?

Slide 25 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4

Slide 26 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen

Slide 27 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock

Slide 28 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine

Slide 29 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine

Slide 30 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting

Slide 31 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia

Slide 32 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine

Slide 33 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl)

Slide 34 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine?

Slide 35 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT?

Slide 36 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry.

Slide 37 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW…

Slide 38 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get

Slide 39 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine

Slide 40 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS

Slide 41 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS

Slide 42 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE

Slide 43 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE

Slide 44 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE

Slide 45 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE

Slide 46 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed)

Slide 47 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY

Ciba markets “Serpasil” : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again

Slide 49 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations.

Slide 50 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom

Slide 51 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom ..a bowl of

Slide 52 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom ..a bowl of After a short-lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming depressed and suicidal Reserpine’s popularity fades

Slide 53 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom ..a bowl of After a short-lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming depressed and suicidal Reserpine’s popularity fades Large contribution to eventual development of catecholamine hypothesis of depression and dopamine hypothesis of psychosis Reserpine’s Relevance

bernard ‘steve’ brodie : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom ..a bowl of After a short-lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming depressed and suicidal Reserpine’s popularity fades Large contribution to eventual development of catecholamine hypothesis of depression and dopamine hypothesis of psychosis Reserpine’s Relevance bernard ‘steve’ brodie Brodie at NIH found that the brains of animals given reserpine had very low levels of 5HT and NE Suggested that reserpine inactivates a mechanism to essential for 5HT storage first demonstration of a link between brain chemistry and behavior

Slide 55 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom ..a bowl of After a short-lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming depressed and suicidal Reserpine’s popularity fades Large contribution to eventual development of catecholamine hypothesis of depression and dopamine hypothesis of psychosis Reserpine’s Relevance bernard ‘steve’ brodie Brodie at NIH found that the brains of animals given reserpine had very low levels of 5HT and NE Suggested that reserpine inactivates a mechanism to essential for 5HT storage first demonstration of a link between brain chemistry and behavior Inhibits ATP/Mg2+ pump responsible for the reuptake of NT into presynaptic vesicles Results in NE and 5HT depletion Reserpine’s Mechanism

Slide 56 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom ..a bowl of After a short-lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming depressed and suicidal Reserpine’s popularity fades Large contribution to eventual development of catecholamine hypothesis of depression and dopamine hypothesis of psychosis Reserpine’s Relevance bernard ‘steve’ brodie Brodie at NIH found that the brains of animals given reserpine had very low levels of 5HT and NE Suggested that reserpine inactivates a mechanism to essential for 5HT storage first demonstration of a link between brain chemistry and behavior Inhibits ATP/Mg2+ pump responsible for the reuptake of NT into presynaptic vesicles Results in NE and 5HT depletion Reserpine’s Mechanism Imipramine A FAILED SLEEP AID AND ANTIPSYCHOTIC

Slide 57 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom ..a bowl of After a short-lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming depressed and suicidal Reserpine’s popularity fades Large contribution to eventual development of catecholamine hypothesis of depression and dopamine hypothesis of psychosis Reserpine’s Relevance bernard ‘steve’ brodie Brodie at NIH found that the brains of animals given reserpine had very low levels of 5HT and NE Suggested that reserpine inactivates a mechanism to essential for 5HT storage first demonstration of a link between brain chemistry and behavior Inhibits ATP/Mg2+ pump responsible for the reuptake of NT into presynaptic vesicles Results in NE and 5HT depletion Reserpine’s Mechanism Imipramine A FAILED SLEEP AID AND ANTIPSYCHOTIC Switzerland 1951 Häfliger and Schinder Synthesize Imipramine

Slide 58 : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine (Prolixin). “ME TOO” DRUGS Further manipulation of this molecular structure yielded numerous other agents with antipsychotic activity. “ME TOO” DRUGS Summary (short version) CHLORPROMAZINE Reserpine A TRANQUILIZING ANTIHYPERTENSIVE (that eventually makes you depressed) Derived from Rauwolfia Serpentina Commonly used antihypertensive in early 1950s Noted to have tranquilizing effects Nathan Kline (of iproniazid fame) published a study in 1954 showing reserpine’s effectiveness in treating psychosis RESERPINE SUMMARY Ciba markets “Serpasil” I couldn’t resist the urge to show this slide again …acts as a gentle mood-leveling agent…sets up needed ‘tranquility barrier’ for many patients who, without some help, are incapable of dealing calmly with a daily pile-up of stressful situations. Give the boy… Alternative to Serpasil for Mom ..a bowl of After a short-lived popularity from 1954 to 1957, the use of reserpine rapidly declined after reports of patients becoming depressed and suicidal Reserpine’s popularity fades Large contribution to eventual development of catecholamine hypothesis of depression and dopamine hypothesis of psychosis Reserpine’s Relevance bernard ‘steve’ brodie Brodie at NIH found that the brains of animals given reserpine had very low levels of 5HT and NE Suggested that reserpine inactivates a mechanism to essential for 5HT storage first demonstration of a link between brain chemistry and behavior Inhibits ATP/Mg2+ pump responsible for the reuptake of NT into presynaptic vesicles Results in NE and 5HT depletion Reserpine’s Mechanism Imipramine A FAILED SLEEP AID AND ANTIPSYCHOTIC Switzerland 1951 Häfliger and Schinder Synthesize Imipramine Swiss firm founded in 1758 Geigy later merged with Swiss firm CIBA to form Ciba-Geigy in 1970 Ciba-Geigy and Sandoz Laboratories merge in 1996 to form Novartis J.R. GEIGY PHARMACEUTICAL FIRM

roland kuhn : Psychopharmacologic Advances 1950-60 Part 2: Iproniazid, Imipramine and Meprobamate Kevin Nasky, DO Not much. WHAT DID WE KNOW IN 1950? Brain was thought to be entirely electrical Acetylcholine was the only known neurotransmitter Knew acetylcholine was inactivated by choline esterase WHAT DID WE KNOW IN 1950? Existence of serotonin in platelets LSD (that it was a hallucinogen and that it was chemically related to 5HT) The enzyme that oxidized adrenaline: “Amine Oxidase” Antihistamines DISCOVERED BEFORE 1950 “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford “When I was an undergraduate student at Cambridge (late 50s) we were taught…there was no chemical transmission in the brain… Neurotransmission was thought to be an entirely electrical phenomena 1950 that it was just an electrical machine” Pharmacologist Leslie Iverson, Professor emeritus, U. of Oxford Acetylcholine was known to be a neurotransmitter, but in the peripheral nervous system only 1950 A lot. WHAT DIDN’T WE KNOW IN 1950? For example… WHAT DIDN’T WE KNOW IN 1950? …as late as 1960, (now Nobel laureate) Arvid Carlsson was practically laughed out of town when he proposed that dopamine might be a neurotransmitter. Since neurotransmitters were not even understood to play any role in the CNS, there was virtually no basis to understand the astounding clinical findings revealed in the decade ahead. WHAT DIDN’T WE KNOW IN 1950? THE CONCEPT OF AN ANTIPSYCHOTIC OR AN ANTIDEPRESSANT DID NOT EXIST HOW WERE WE TREATING MENTAL ILLNESS IN 1950? Most “treatments” were simply measures to sedate patients in overcrowded asylums. Physical Methods Insulin coma ECT Leucotomy Bromides Barbiturates Paraldehyde Opioids Psychotropic Methods Psychosis Depression Anxiety TREATMENTS OF CHOICE Insulin Coma Deep Sleep ECT Opioids Various meds Leukotomy Chlorpromazine and Reserpine A QUICK REVIEW… Chlorpromazine IN SEARCH OF BETTER ANTIHISTAMINES What do Benadryl, Phenergan, Thorazine and Tofranil have in common? Speaking of Antihistamines… Definitely not their indications: allergies, nausea, psychosis and depression, respectively. Speaking of Antihistamines… A (very) short course in the chemistry of antihistamines: How Benadryl became Thorazine (well, sort of) Simple. 4 Easy Steps… HOW DO YOU MAKE AN ANTIHISTAMINE? Start with a substituted ethyl amine Substitute methyl or other short alkyl groups in R1 and R2  X = C, O or N  Add an aryl group at R3 and R4 Example: diphenhydramine Aryl groups at R3 & R4 Methyl groups at R1 & R2 X = oxygen henri laborit Experimented with various phenothiazine anti-histamines in his lytic cocktails to reduce analgesia required in effort to reduce surgical shock paul charpentier Charpentier synthesized a series of phenothiazines that were strongly antihistaminergic. The most prominent of these was promethazine Rhône-Poulenc chemist phenothiazine expert synthesized the first tricyclic antihistamine, promethazine Promethazine fits the classic structure of an antihistamine Flight Plan for Anesthetic Objective “…like a conscientious airman [the anesthesiologist] previously has filed a flight plan that, when carefully followed, leads to the objective…” To relieve apprehension To produce light sleep To reduce the incidence of nausea and vomiting Laborit wonders if there’s an even better compound than promethazine for his "lytic cocktail" Patients given promethazine were more calmer after surgery, needed less post-op morphine and anesthesia henri laborit Laborit asks Rhône-Poulenc to make a more centrally-acting antihistamine PROMAZINE Replaced isopropyl group with a straight carbon chain propyl propyl (3-carbon alkyl) Laborit has good results with Promazine, but said it was too weak. Asks Charpentier: Can you make me a stronger Promazine? It was well known that adding a halogen to an organic molecule usually increased its potency and toxicity… HOW DO YOU MAKE PROMAZINE MORE POTENT? CHLORpromazine so Charpentier added one chloride atom to Promazine and forever changed psychiatry. Replace one sulfur atom… BTW… …with an ethylene linkage, preventing formation of the benzene ring and you get imipramine Replace the chlorine in chlorpromazine with a trifluoromethyl group, and you get trifluoperazine (Stelazine).