Medicinal Chemistry Exam 1 Review with answers

Medicinal Chemistry : Medicinal Chemistry Exam 1 Review Session Rho Chi Fall 2011 September 21, 2011

Rho Chi : Rho Chi Facebook: http://www.facebook.com/Rho.Chi.MCPHS/ Website: http://bit.ly/rhochi-review

Objectives : Objectives Nomenclature parent nucleus functional group names Henderson-Hasselbalch Drug distribution, PPB Phase 1 and phase 2 metabolism Some study tips

Nomenclature : Nomenclature Parent nuclei Functional groups Numbering/lettering

Ring structure nomenclature : Ring structure nomenclature 5-membered rings (ending with “-ole”) Unsaturated systems (2 double bonds) = ~OLE Partially saturated systems (1 db) = ~OLINE Saturated systems (no db) = ~OLIDINE 6-membered rings = ~INE 7-membered rings = ~EPINE

Ring structures to memorize : Ring structures to memorize 5-membered rings Furan Thiophene Pyrrole imidazole 6-membered rings Pyridine, piperidine Pyrazine, piperazine Pyridazine Pyrimidine Heterocyclic rings Quinoline Indole Benzimidazole Purine Phenothiazine

Name this molecule : Name this molecule

And this one : And this one

What ring systems are found in nicotine? : What ring systems are found in nicotine? Pyridine Piperidine Pyrimidine Furan Pyrrole 1,5 2,5 1 5 None of the above

Numbering fused-ring systems : Numbering fused-ring systems Look for 1st atom outside fusion site. Number around the molecule moving away from the fusion site. Skip the fusion sites. Benzo-b-1,4-diazepine

Lettering fused-ring systems : Lettering fused-ring systems Determine which of the first atoms from the fusion point to start numbering from. Do not start lettering from center ring. Choose an atom that will give the heteroatom the lowest #. Start lettering sides from heteroatom to give the fused sides the lowest possible letter. Dibenzo-b,f-azepine

What is the parent nucleus for chlorpromazine (Thorazine®)? : What is the parent nucleus for chlorpromazine (Thorazine®)? phenothiazine

What is the parent nucleus for clozapine? : What is the parent nucleus for clozapine? Dibenzo[b,f]-1,4 diazepine Dibenzo[b,e]-1,4 diazepine Dibenzo[b,e]-1,5 diazepine Dibenzo[b,f]-1,5 diazepine

Functional groups : Functional groups Acidic groups (form basic salts) Carboxyl Sulfonamide Imide Phenolic Basic groups (form acidic salts) Aliphatic amines Pyridine type Aniline type Neutral groups Amide Pyrrole Quaternary amine

Functional groups : Functional groups Hydroxyl – very polar Aliphatic alcohols Phenols Amino – very polar Carboxyl – weakly polar Alkyl – very lipophilic, well absorbed Ester - the presence of more carbons makes esters more lipophilic and therefore better absorbed. Halogens – increase lipophilicity

What functional groups are found on diltiazem? : What functional groups are found on diltiazem? Ether Ester Sulfonamide Tertiary amine Quaternary amine 1, 2, 5 1, 2, 4 2, 3, 4 2, 3, 5 All of the above

Rank the following molecules in increasing order of polarity : Rank the following molecules in increasing order of polarity 1 < 2 < 3 2 < 3 < 1 2 < 1 < 3 1 < 3 < 2 3 < 1 < 2

Would you expect hydrochlorothiazide to be formulated as an acidic or basic salt for IV administration? : Would you expect hydrochlorothiazide to be formulated as an acidic or basic salt for IV administration? Basic (sodium) salt Sulfonamides are weakly acidic

Which of the following are acidic drugs? : Which of the following are acidic drugs? Codeine sulfate Naproxen sodium Fluoxetine hydrochloride Divalproex sodium Potassium chloride a. 1, 2, 3 b. 2, 3, 4 c. 2, 4 d. 1, 3, 5 e. 3, 5

Henderson-Hasselbalch : Henderson-Hasselbalch The basic idea: As pH increases, species tend to lose their protons (H+) When a species’ pKa = pH, 50% of the molecules are protonated Acids are neutral when protonated = HA Bases are positively charged when protonated = HB+

HH & Absorption : HH & Absorption Only non-charged species can cross membranes Acids are neutral (absorbed) at pHpKa

pH scale : pH scale

In the stomach (pH = 2) what % of naproxen sodium (pKa=4.5) is available for absorption? : In the stomach (pH = 2) what % of naproxen sodium (pKa=4.5) is available for absorption? We know that naproxen is an acidic drug because it is the form of a sodium salt = Na+ A-

In the stomach (pH = 2) what % of naproxen sodium (pKa=4.5) is available for absorption? : In the stomach (pH = 2) what % of naproxen sodium (pKa=4.5) is available for absorption? pH = 2

In the stomach (pH = 2) what % of naproxen sodium (pKa=4.5) is available for absorption? : In the stomach (pH = 2) what % of naproxen sodium (pKa=4.5) is available for absorption? 0-1% 1-10% 10-50% 50-90% 90-100%

How much morphine sulfate (pKa = 9) will be absorbed in the blood (pH = 7.4)? : How much morphine sulfate (pKa = 9) will be absorbed in the blood (pH = 7.4)? We can tell morphine is a basic drug because it is in the form of an acidic salt (B+ SO4-2)

How much morphine sulfate (pKa = 9) will be absorbed in the blood (pH = 7.4)? : How much morphine sulfate (pKa = 9) will be absorbed in the blood (pH = 7.4)? pH = 7.4

How much morphine sulfate (pKb = 5) will be absorbed in the blood (pH = 7.4)? : How much morphine sulfate (pKb = 5) will be absorbed in the blood (pH = 7.4)? 0-1% 1-10% 10-50% 50-90% 90-100%

Calculate whether phenytoin is better absorbed in the stomach (pH 1), the duodenum (pH 4),or the upper intestine (pH 8). : Calculate whether phenytoin is better absorbed in the stomach (pH 1), the duodenum (pH 4),or the upper intestine (pH 8).

Calculate whether phenytoin is better absorbed in the stomach (pH 1), the duodenum (pH 4),or the upper intestine (pH 8). : Calculate whether phenytoin is better absorbed in the stomach (pH 1), the duodenum (pH 4),or the upper intestine (pH 8). pH=1 pH=4 pH=8

Drug distribution & Plasma Protein Binding : Drug distribution & Plasma Protein Binding A drug dissolutes and is then absorbed into the blood The amount that makes it into the blood is termed the drug’s bioavailability Plasma proteins can bind to and facilitate a drug’s movement throughout the body The main PP is albumin which binds drugs that are: Lipophilic acidic

Drug distribution, PPB : Drug distribution, PPB Most drugs are bound to PPB and only a small % is unbound Unbound drug = free drug Only free drug can bind to its receptor Once the drug enters circulation it is distributed throught the body

Receptors : Receptors Drugs can interact with their receptors via London forces (eg. –CH3) H-bonding (eg. -OH) Ionic bonding (eg. -NH3+, -COO-) Receptors are also specific to a molecule’s chirality

What kind of bonding do you expect at dopamine’s receptor at pH = 4, pKa = 8? : What kind of bonding do you expect at dopamine’s receptor at pH = 4, pKa = 8? H-bonds London forces Ionic bonds 1 and 2 All of the above

Phase 1 and phase 2 metabolism : Phase 1 and phase 2 metabolism Phase 2 Conjugation: Enzymes convert now-polar molecule into water -soluble molecule Phase 1 – makes the molecule more polar Microsomal - liver Non-microsomal – liver and elsewhere (GIT, plasma, etc.)

Phase 1 metabolism : Phase 1 metabolism Microsomal enzymes (CYP450) Aliphatic hydroxylation Aromatic hydroxylation N,O,S-dealkylation Oxidative deamination Nonmicrosomal enzymes Monamine oxidases Estrases Amidases Alcohol dehydrogenases

What are some possible routes of metabolism? : What are some possible routes of metabolism? CYP Aromatic hydroxylation Aliphatic hydroxylation N-dealkylation

In the structure below, where is aromatic hydroxylation most likely to take place? : In the structure below, where is aromatic hydroxylation most likely to take place? A) A B) B C) C D) D E) E F) F

What are some possible routes of metabolism? : What are some possible routes of metabolism? CYP Aromatic hydroxylation Deamidation Non-microsomal? MAO?

Estrases are enzymes that can be found in the _______. : Estrases are enzymes that can be found in the _______. A) Liver B) Brain C) Circulatory System D) All of the Above

What are some possible routes of metabolism? : What are some possible routes of metabolism? CYP N-dealkylation Aromatic hydroxylation Nonmicrosomal Estrase

Phase 2 metabolism : Phase 2 metabolism Occurs mainly in liver (some in kidney) Makes molecule more polar so it can be excret Conjugate molecule with UDP (primarily) Drugs that undergo phase 2 metabolism have either: OH COOH

Questions? : Questions?