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Experimental Pharmacology

Question 1 is a calculation question. It offers 50% of the paper’s marks and is COMPULSORY.
Then answer 2 from 5 further questions – only 2 examples are shown here. 25 marks per question.

Question 1.
Background: an experiment was performed to measure efficacy and the EC50 (the concentration of drug that evokes a half its maximal response) of the drugs acetylcholine and butyrylcholine in strips of smooth muscle the porcine urinary bladder.
Table 1 – response (mN) to acetylcholine (ACh) and butyrylcholine (BCh) in bladder strips. Data expressed as mean±SEM (n=3).
LogFBC ACh (mN) SEM BCh (mN) SEM
-8.000 0.00 0.00 0.00 0.00
-7.699 9.00 1.73 7.00 0.82
-7.398 29.33 3.18 21.50 1.22
-7.097 39.33 1.76 27.00 1.63
-7.000 54.00 2.89 35.00 0.82
-6.699 61.33 3.18 38.50 1.22
-6.398 97.67 3.18 60.50 1.22
-6.097 117.00 2.65 71.50 2.04
-6.000 139.67 2.91 88.00 1.63
-5.699 149.33 3.76 92.50 2.04
-5.398 152.67 3.48 95.50 2.04
-5.097 153.67 3.48 96.00 2.45

a) What is the pharmacological role of acetylcholine in the experimental protocol? (1 mark)

b) Which receptor type does acetylcholine act on in bladder smooth muscle? (2 marks)

c) Using the data in Table 1, plot cumulative dose-response curves to acetylcholine (ACh) and Butyrylcholine (BCh). (20 marks)

d) Calculate the EC50 value for acetylcholine under each condition. (8 marks)

e) How does atropine have its effect in this system. (3 marks)

f) What is the affinity of atropine for its target in this system? Show your workings. (15 marks)
Question 2.
Describe the structure and properties of ligand-gated ion channels. (25 marks)

Question 3.
Explain the biochemical events regulating heart muscle contraction. (15 marks)
How do calcium channel blockers and muscarinic receptor agonists prevent this from occurring? (10 marks)
iv) The following data was obtained for a series of novel analogues which have been evaluated for activity at adenosine receptors and their ability to stimulate release of hormone I in vivo. These analogues have been developed from a parent compound (compound A) with the aim of producing compounds with greater selectivity and efficacy.

Kd at A receptors (nM)
DRUG A1 A2 A3 Kd at M1 muscarinic receptors (nM) Hormone I Secretion
ng/ml Efficacy index Breakdown
by enzymes
%
Compound A
1456 4779 212 >10 000 323 0.81 8
Analogue 1
64 28 93 288 394 23
Analogue 2
1667 3870 4987 >10 000 21 10
Analogue 3
1610 2298 15 >10 000 387 7
Analogue 4
1826 4400 13 >10 000 0 9.5
Analogue 5
2002 5536 14 >10 000 376 96.3
Analogue 6 2315 3526 40 >10 000 145 14.2

ANSWER THE FOLLOWING:-

v) Given that an efficacy index of 1 corresponds to secretion of 400ng/ml of hormone I (the maximum achievable secretion), calculate the efficacy index for each analogue. (3 marks)

vi) Describe the activity profile of each analogue (1-6), and comment on its suitability for further evaluation. (2 marks each)
B3) Write a short essay on TWO of the following:

a) “Finding a lead compound” – as a guide ensure that you make
reference to each of the following: clinical lead, drug target,
bioassay, structure activity, pharmacophore.
b) Target specificity and selectivity between species. Illustrate
your answer
with a suitable example.
c) Combinatorial synthesis

(2 x 10 marks)
B4) Write a short essay on TWO of the following:

a) Toxicity testing – as a guide, ensure that you cover the following points in
your answer: animal testing, lethal dose curve, LD50 values.
b) Development of drugs from natural sources
c) High throughput screening and screening by NMR spectroscopy