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9133 Final Exam, Semester 1, Medicinal Chemistry 3A 2006 Page 1 of 16

THE UNIVERSITY OF SYDNEY

FACULTY OF PHARMACY

BACHELOR OF PHARMACY DEGREE

THIRD YEAR EXAMINATION

PHAR 3609 MEDICINAL CHEMISTRY 3A

SEAT NUMBER: ………………………………………… SURNAME:……………………………………………….. OTHER NAMES:………………………………………….. June 2006 Time allowed: 1.5 hours (also 10 minute reading time) • Use the SHEET provided to mark clearly in pencil your answer to the multiple choice questions, 1 to 21. • All written answers to questions 22-28 must be completed on the question paper (pages 8-16). • The value of each question is shown in the table below and on the paper against questions 22 to 28. • Marks will NOT be deducted for incorrect answers in the multiple choice questions.

Question Marks Actual Mark 1-21 42 22 12 23 4 24 4 25 6 26 4 27 4 28 4 TOTAL 80

• This examination booklet consists of 16 pages, numbered from 1-16 inclusive. There are 28 questions numbered from 1-28 inclusive.

• Students are asked to check that their booklet is complete, and to indicate that they have done so by signing, as provided below.

• Students finding an incomplete booklet should obtain a replacement from the Examination supervisor immediately.

I have checked this booklet and affirm that it is complete. SIGNATURE .....................................................................................................


Question 1 Which of the following statements are CORRECT? Non-steroidal anti-inflammatory drugs A. inhibit production of leukotrienes B. are antagonists of eicosanoids in their binding to nuclear receptors C. inhibit the conversion of arachidonic acid to oxidized, cyclized products D. are antagonists of prostaglandins in their binding to membrane receptors E. activate the hydrolysis of polyunsaturated fatty acids from membrane phospholipids Question 2 The largest group of non-steroidal anti-inflammatory drugs are the arylalkanoic class of drugs. Which of the following statements are CORRECT? A. B. C. D. E.

The class name for aryl- and heteropropionic acids is “profens” Arylalkanoics are reversible, competitive inhibitors of COX-1 and COX-2 Arylalkanoics are irreversible, non-competitive inhibitors of COX-1 and COX-2 Diclofenac inhibits the cyclooxygenase pathway only A and B are correct

Question 3 An element with a deficiency of neutrons can decay to a more stable nuclide by A. emission of a helium atom B. capture an electron from an internal electron shell to form a neutron C. decay of a proton to a neutron and a positron which is expelled D. capture an electron from an internal electron shell to form a proton E. Both B and C are correct Question 4 During the process of annilation radiation A. A positron leaves the nucleus B. A positron loses kinetic energy by interacting with surrounding atoms C. A positron combines with an e-

D. 2 photons that travel in opposite directions are formed E. All of the above Question 5 Beta particles, A. consist of an electron B. due not travel very far through space because of their relatively large size which results in

many collisions C. may lead to ionisation of other molecules D. Answers A and C are correct E. Answers A, B, and C are all correct


Question 6 A radionuclide ideal for use in a daughter nuclide generator has the following properties A. Grand-daughter nuclide is very long-lived or stable B. Daughter half life is longer than parent half-life C. Long Parent nuclide half-life D. The daughter nuclide is a pure gamma-emitter E. Answers A and D are both correct The following relates to the next four (4) questions (i.e. Questions 7 – 10): A 99Mo/99mTc generator is loaded with 24 GBq of molybdenum-99 as MoO3 at 9am on Wednesday May 17 before dispatch to the Nuclear Medicine Department. The first elution is made in the Radiopharmacy at 9am on Thursday May 18. An elution volume of 15 mL is used with an extraction efficiency of 85%. Data t1/2 99mTc = 6 h, 99Mo = 67 h Question 7 The amount of material that 24 GBq of 99Mo represents is closest to: A. 1.4 ng B. 2.4 ng C. 0.14 µg D. 1.4 µg E. 2.4 mg Question 8 The activity in MBq per ml of the eluate drawn at 11am on Thursday May 18 is closest to: A. 750 B. 1000 C. 1550 D. 1800 E. 95000 Question 9 The volume in mL of this eluate which must be dispersed for a skeletal scan requiring 250 MBq of 99mTc at 4 pm on Thursday May 18 is closest to: A. 0.1 B. 0.3 C. 0.5 D. 0.7 E. 0.9


Question 10 The maximum dose of 99mTc in MBq that can be given in a 2ml injection at 11 am on Friday May 19 is closest to: A. 400 B. 800 C. 1600 D. 2000 E. 2400 Question 11 Terfenadine (R=CH3) and Fexofenadine (R=COOH) are both second generation antihistamines, which of the following statements are INCORRECT.

NOH CH3

CH2 CH2 CH2 CH

OH

RCH3

A. Fexofenadine metabolised in body to Terfenadine B. Terfenadine metabolised in body to Fexofenadine C. Fexofenadine does not have a sedative action D. Terfenadine is extremely cardiotoxic E. Answers B, C and D are all incorrect. Question 12 Thiaburimamide (A) is more active than burimamide because (B).

CH2CH2

CH2

CH2

HN

HNN

NHMe

S

CH2S

CH2

CH2

HN

HNN

NHMe

SA B

A. Because the sulfur atom results in a change in the preferred conformation of the side chain B. Because the sulfur is electron donating and results in a decrease in the pKa of the imidazole ring C. Because the sulfur is electron donating and results in an increase in the pKa of the imidazole

ring D. Because the sulfur is electron withdrawing and results in a decrease in the pKa of the imidazole

ring E. Because the sulfur is electron withdrawing and results in an increase in the pKa of the

imidazole ring


Question 13 When 4-methyl histamine is protonated to form a cation at N-α, in solution A. The Nτ-H tautomer is preferred because the methyl group is electron withdrawing B. The Nτ-H tautomer is preferred because the methyl group is electron donating C. The Nπ-H tautomer is preferred because the methyl group is electron withdrawing D. The Nπ-H tautomer is preferred because the methyl group is electron donating E. The tautomers (Nπ-H and Nτ-H) are present in equal amounts Question 14 Very Low Density Lipoproteins (VLDL) transport A. dietary triglycerides to adipose tissue and muscle for hydrolysis by lipoprotein lipase B. endogenous triglycerides to adipose tissue and muscle for hydrolysis by lipoprotein lipase C. endogenous cholesterol for conversion to LDL D. endogenous cholesterol for receptor-mediated endocytosis by the liver E. dietary cholesterol to the liver for receptor-mediated endocytosis Question 15 Homozygous familial hypercholesterolemia is caused by A. Genetic mutation of apolipoprotein B-100 B. a total lack of LDL receptors C. a deficiency of lipoprotein lipase D. a deficiency of apolipoprotein E E. a deficiency of LDL receptors Question 16 In addition to their chloesterol-lowering effects, statins have been reported to exert significant cardiovascular protective effects by A. stimulating leukocyte-endothelial cell interaction during inflammation B. improving the stability of the mRNA for endothelial nitric oxide (NO) synthase C. promoting the synthesis of NO by endothelial cells D. stimulating the release of prostacyclin, an endothelium –derived mediator E. Both B and C are correct


Question 17 Compared to other HMG CoA reductase inhibitors, pravastatin has enhanced hydrophilicity due to its

A. carboxylate group B. 3,5-dihydroxyl groups C. 6’-hydroxyl group D. A and C are correct E. A, B and C are correct Question 18 Similar to HMG CoA reductase inhibitors, the active forms of all fibrates A. contain a carboxylic acid B. contain an isobutyric acid group C. contain a phenoxyisobutyric acid group D. are primarily ionized at physiologic pH E. also lower cholesterol

Question 19 Which of the following statements are INCORRECT? The Angiotensin-converting enzyme (ACE) is a relatively non-specific dipeptidyl carboxypeptidase which A. contains one zinc atom per molecule B. inactivates bradykinin, a potent vasodilator C. requires only a tripeptide sequence as a substrate D. does not metabolise Angiotensin II because its penultimate amino acid is not proline E. produces Angiotensin II, a potent vasoconstrictor

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Question 20 Which of the following statements regarding cholestyramine or colestipol are CORRECT?

A. They are chemically classified as cation-exchange resins B. The chloride groups of cholestyramine can be displaced by bile acids C. The quaternary ammonium groups of cholestyramine function as binding sites for glycocholic

acid D. The amines on colestipol can be displaced by taurocholic acid E. Both B and C are correct

Question 21 Enalapril, the prodrug of the angiotensin-converting enzyme (ACE) inhibitor, enalaprilat has superior oral bioavailability due to A. the presence of two carboxylate groups B. the high pKa of its secondary amine functional group C. its capacity for zwitterion formation D. its amine being primarily unionised in the small intestine E. its esterification by hepatic esterases

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Question 22 (12 marks in total) NSAIDs work by inhibiting the actions of cyclooxygenases (COX). a) Outline the differences between the COX-1 and COX-2 isoforms, focusing on physiological function and structure (4 marks).


b) Detail the common structural features of NSAIDs using aspirin as an example (2 marks). c) Explain why a number of NSAIDs cause gastric ulcerations and name TWO therapeutic approaches that can be taken to reduce this side effect (2 marks).


d) The action of cyclo-oxygenase on arachidonic acid produces a number of prostanoids. Outline the role of prostanoids in health and disease and discuss the current biological theories behind the adverse cardiovascular events linked to COX-2 inhibitors (4 marks).


Question 23 (4 marks) Outline 2 different mechanisms through which radiopharmaceuticals can be distributed in the body, give examples of how these mechanisms are used to obtain diagnostic images.


Question 24 (4 marks) Give examples of 3 quality control issues surrounding the production of radionuclides and the techniques used to ensure the quality and radiopurity of the nuclides.


Question 25 (6 marks) Describe the general pharmacophore of H3 antihistamines.


Question 26 (4 marks) Outline the general structural features of 1st generation H1 receptor antagonists.


Question 27 (4 marks) Like HMG CoA reductase inhibitors or statins, bile acid sequestrants (BAS) lower plasma low density lipoprotein (LDL) by a LDL receptor-mediated mechanism. Explain what this means in relation to what is known regarding the mechanism of action of BAS.


Question 28 (4 marks) Discuss the structural features of the angiotensin-converting enzyme (ACE) inhibitor, enalprilat which are essential for optimum inhibition of ACE and the function of each structural feature in relation to ACE (4 marks)

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