Responses to Agonists

Question 1

Explain agonist-receptor binding using the law of mass action. Reference KD and what it means.

Answer 1

Law of Mass Action = The rate of a reaction is proportional to the molecular concentration of the reactants.

KD is a measure of affinity; measured as a concentration (M)

• Higher affinity of a drug for a receptor = lower value of KD
• Measures conc. of drug that occupies 50% of binding sites at equilibrium

Question 2

Explain the relationship between receptor occupancy and drug concentration.

Answer 2

If response is proportional to occupancy then the Hill-Langmuir equation can also be used to relate concentration to response.

Question 3

Explain the relationship between drug occupancy and response to explain how potency is measured.

Answer 3

Potency measured as:

- EC50 = concentration of drug that produces 50% of the maximal response

Question 4

Describe the important features of the agonist dose-response curve and use these features to compare different agonists in terms of potency and intrinsic efficacy.

Answer 4

Full agonist = peaks at Emax, 70% straight line

Full agonist with lower affinity = peaks at Emax, 70% straight line but shifted to the right (higher EC50)

Partial agonist = never reaches Emax

Question 5

Describe the Hill coefficient and what it measures.

Answer 5

nH = Hill coefficient (describes cooperativity)
o n > 1 - positive cooperativity
o n = 1 - noncooperative binding
o n < 1 - negative cooperativity

Question 6

Explain why a drug’s potency may not necessarily be the same concentration as its affinity. Think in relation to partial agonists and spare receptors.

Answer 6

Partial Agonists

• Produces only a partial (sub-maximal) response, even when all receptors are occupied (bound)
• Intrinsic efficacy >0, <1

Spare Receptors
- However, some drugs elicit maximal response when fewer than 100% receptors are occupied – remaining receptors are “spare” receptors