Name: _______________________________ Student ID# __________________________

Intro. to Medicinal Chemistry CHEM 640 EXAM 1.0 Feb 26, 2004

----------------------------------------------------------------------------------------------------------------------------------1. To the right, is a doseA A B B 100 response graph for two hypothetical hypnotic drugs 80 (A and B) used in a truth 60 death serum by a hypothetical hypnosis 40 government agency when interrogating hypothetical 20 political prisoners. At low 0 concentrations, hypnosis 0 5 10 15 20 25 30 35 occurs while at higher dose (mg) concentrations, each drug causes death.
(7 pts)

A. Calculate the therapeutic index for both compounds (A and B).

B. Based upon their therapeutic index values, which compound has a greater margin of safety? 2. Assume that the compound shown here is a novel lead drug. There are a few major functional groups on this drug that may be responsible for activity .
(18 pts)
HO

A. What individual chemical reactions would you perform to specifically determine the necessity of each group? Show both the chemical reagents you would use and the resulting products. (Use the reverse side of the page if necessary)

N H3 C

B. Assume that each of your modifications destroyed the activity of the drug. Propose how each of these groups were involved in binding to the target receptor.

3. As you know, morphine is a powerful analgesic. Researchers found that when the N-methyl group of morphine was replaced with a phenethyl group, analgesic activity increased 14-fold. Provide an explanation for this enhancement of potency.
(5 pts)

N A HO O morphine OH D B C

CH3 A HO O D B C

OH N-phenethyl morphine

4. For the hypothetical compound shown below, suppose that when X = CH2 and n = 2, the binding to a receptor and consequently, pharmacological activity is greater than when X = CH2 and n = 1. However, when X = O (oxygen) and n = 1 both receptor binding and pharmacological activity is lower than when X = CH2 and n = 1. Propose two different reasons why the isosteric replacement of the N H methylene group (CH2) with oxygen (O) diminishes the activity. Please use X N N figures to illustrate your explanation. H n
(10 pts)
X = CH2 or O n = 1 or 2 O

5.

Sanfetrinem Cilexetilis a prodrug of Sanfetrinem. OH OH Propose how the prodrug form of Sanfetrinem is activated. Please show all steps involved and N N indicate which ones are enzyme catalyzed and O CH3 O CH3 O O which ones are spontaneous. Please show all side O O O O OH products of the activation process. To help you O O complete this question in a timely manner, you may Sanfetrinem Cilexetil Sanfetrinem abbreviate the Sanfetrinem structure as DrugCO2H and intermediate structures in the activation process may be derivatives of this abbreviation.

(10 pts)

6. The alkaloid sfsuscine was recently isolated from an unusual mold growing in a coffee cup. A student noted that sfsuscine showed both moderate antidepressant and hallucinogenic properties. It was noted, that when the amino group on sfsuscine was positively charged, its antidepressant properties were reduced but its hallucinogenic properties were enhanced. H + N Furthermore, it was determined that a decrease in X + H Ka N X sfsuscines partition coefficient (P) resulted in a dramatic decrease in both antidepressant and sfsuscine hallucinogenic activity.
(16 pts)

A. Based upon the table below, what single group would you incorporate on the aromatic ring of sfsuscine in order to enhance its hallucinogenic property while reducing its antidepressant property? (Draw the chemical structure) Group HO CH3 H F Cl Br CH3C(O) para -0.38 -0.14 0 0.15 0.24 0.26 0.47 meta 0.13 -0.06 0 0.34 0.37 0.37 0.36 para -0.61 0.52 0 0.15 0.73 0.98 -0.37 meta -0.49 0.51 0 0.15 0.73 0.98 -0.28

B. In contrast to Question A, draw the structure of a disubstituted sfsuscine analog that would elicit the enhanced antidepressant activity. Remember and effects are additive and that successful antidepressants should be able to readily cross the lipophilic blood-brain barrier.

C. If one were to plot log(KaX / KaH) for sfsuscine vs. , would you expect > 0 or < 0 ?

7. Bioavailability is influenced by several factors including the route of administration. We have studied that through some routes of administration, a drug may suffer first-pass effects.
(9 pts)

A.

Briefly define or describe first-pass effect.

B. C.

List a route of drug administration that suffers first-pass effects. List a route of drug administration that does not suffer first-pass effects.

8. Briefly describe the difference between Phase I and Phase II metabolism.

(4 pts)

9. The compound here is a well-known and potent cocaine analog.

(9 pts)

H3 C

O OCH3

A. To the best of your ability, draw the chemical structures of 2 possible Phase I metabolites for the following compound. Each structure should include only one metabolic modification.

WIN 35,065-2 (potent cocaine analog)

B. For one of the above metabolites in Part A, draw one subsequent Phase II metabolite.

10. For the following questions, consider Phase II metabolism.

(12 pts)

A. Below are 3 coenzyme forms required for certain Phase II conjugation reactions. For each, circle only the portion of the coenzyme that is transferred during metabolism.
NH2 CH3 HO2 C NH2 H2 O3 PO S
+

N O N N

HO2 C HO HO HO O

O O P HO O O P HO O N NH O

OH

HO OH

CoA

B. How do the substrates for glutathione conjugation differ from the substrates for conjugation reactions with the above coenzymes.