MED. CHEM. I - FINAL EXAM
PRACTICE

Answers are given in RED!

Answer the following questions that refer to the 16 structures shown here (click to view).

1. List a structural class for each drug.

Refer to appropriate pages in Lecture Guide.

2. List those structures that will form pharmaceutically-useful salts with HCl.

#2, 3, 4, 11, 12, 13, 15

3. List those structures that will form pharmaceutically-useful salts with NaOH.

#5, 7, 13

4. List those structures that are neutral (pharmaceutical sense).

#1, 6, 8(?), 9, 10, 14, 16

5. List those structures that will undergo chemical hydrolysis (in vitro).

2 (anilide), 7 and 9 (imides), 8 (amide), 10 (phosphate ester)

6. List those structures that can exhibit optical isomerism.

#1, 2, 3, 4, 7, 8, 9, 13, 16

7. List those structures that can exhibit geometric isomerism.

#1, 3, 4, 11, 16

8. Locate and label ONE example of each of the following groups in the structures. (refer to PY419 notes)
a. 3°-amine
b. 4°-ammonium group
c. Carboxyl group
d. 3°-alcohol
e. amide
f. phenolic hydroxyl
g. imine function
h. thiophosphate ester
i. 1°-amine
j. imide function

9. List the primary pharmacological action of each of the structures. 

#:		Pharmacological		#:		Pharmacological
1 General anesthetic 9 Anticonvulsant 2 Local anesthetic 10 Cholinomimetic, indirect 3 Narcotic analgesic 11 Antidopaminergic 4 Narcotic antagonist 12 Biogenic amine reuptake 5 NSAID Inhibitor 6 Sedative/hypnotic 13 Biogenic amine precursor 7 Sedative/hypnotic 14 Cholinolytic, anti-MAChR 8 Sedative/hypnotic 15 Cholinolytic, anti-MAChR anxiolytic 16 Cholinolytic, anti-NAChR

10. BRIEFLY describe a mechanism of pharmacological action for each of the structures.

Refer to appropriate chapters in Lecture Guide.

11. List ONE therapeutic use for each of the structures. 

#:		Therapeutic		#:	Therapeutic
1 General anesthesia 9 Antiepileptic 2 Local anesthesia 10 Glaucoma 3 Pain relief 11 Antipsychotic 4 Opiate antidote 12 Depression 5 Arthritic disorders 13 Parkinson's 6 Insomnia Disease 7 Insomnia 14 GI antispasmodic 8 Anxiolysis 15 Antiparkinson 16 Muscle relaxant
12. Show the structure of ONE likely Phase I metabolite for each of the structures.

Click here for structures.

13. Drug #1 is unstable in alkali. Show a likely reaction for this structure at alkaline pH. Under what circumstances might this drug come into contact with alkaline material?

Alkali is used to remove CO2 from the patient's expirations. Any of the inhalation general anesthetic in these expirations can react chemically with the alkali.

14. The onset of pharmacological action of drug #2 is significantly more rapid when this drug (as its HCl salt) is injected in a pH 6.5 buffered solution compared to injection of a nonbuffered solution of drug #2 HCl salt (pH 5.2). Explain why?

There will be higher concentrations of the unionized LA in the pH 6.5 solution allowing more rapid penetration of the drug to the intramembranal ion channel site of action.

15. What structural feature of drugs 3 and 4 is responsible for the different pharmacological actions of these drugs?

Structural features of the N-substituent determine if the drug is an opiate agonist (R=CH3) or an opiate antagonist (R=CH2CH=CH2)

16. Drug #5 has a relatively short elimination t½. Draw the structure of an analogue of this structure that will possess a longer duration of action.

17. Drug #6 is a prodrug. What is a prodrug? Show the biochemical reactions associated with the pharmacological actions of drug #6.

A prodrug, in itself, lacks pharmacological activity but must be bioactivated after administration via host metabolic/chemical processes.

Cl3C-CH(OH)2 <----> Cl3C-CHO -[H]-> Cl3C-CH2OH

18. Classify structure #7 on the basis of duration of action (check one of the following):

Structure #7 is a thiobarbiturate therefore of high lipid solubility and ultra-short duration of action due to rapid tissue redistribution.

19. Draw the structure of an analogues of drug #8 that will have a longer duration of action.

20. Draw the structure of a metabolite of drug #9 that will bind to plasma proteins.

21. Illustrate the mechanism of pharmacological action of structure #10 using chemical reactions. Chemically show how enzyme ageing may occur as a component of the action of structure #10. Chemically show how 2-PAM functions to reverse the biochemical effects of structure #10.

Refer to diagrams on page 104 (revised) of lecture guide for chemical mechanisms of organophosphate inhibition of AChE and subsequent ageing of the OP-AChE complex.

22. Would you expect structure #11 to possess a high SDA ratio? Explain your answer.

Drug #11 is a phenothiazine derivative which characteristically have high dopaminolytic activity and relatively low activity at serotonin receptors. Hence, it would be anticipated that these antipsychotics will have low serotonin-dopamine antagonistic ratios unlike the newer antipsychotics (risperidone, olanzapine) which were developed specifically for their high anti-serotonin activities (high SDA ratios).

23. Draw the structure of an analogue of structure #12 that would have higher potency and more useful in patients with retarded depression. Explain your answer.

2º-amine TCADs have greater selectivity for blockade of NE reuptake and are generally more potent antidepressants with lesser incidences of sedation and cardiovascular side effects.

24. Show the structure of each metabolite formed from structure #13 by the action of the following enzymes.
a. Aromatic amino acid decarboxylase
b. Catechol-O-methyl transferase
c. Monoamine oxidase

25. Describe the 4 components of the structure of drugs #14 and #15 that contribute to their pharmacological activity. Which structure, 14 or 15, would be most useful in treating the symptoms of Parkinson's Disease. Explain your answer.

Drug #14, a 3º-amine antimuscarinic will possess sufficient liposolubility to enter the CNS via the BBB and access nigrostriatal pathways. Drug #14, a 4°-ammonium salt, is too polar for distribution to the CNS.

26. Show the products of a Hofmann Elimination reaction of structure #16. Comment on the possible therapeutic significance of this reaction.

This drug will biodegrade primarily by a chemical versus metabolic process therefore providing highly predictable duration of muscle paralysis in treated patients.

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