SL12100

LECTURE 17: RECEPTOR ANTAGONISTS AND MODULATORS – TUNING A RESPONSE

1. What is an antagonist?
Antagonist = a ligand that binds to a receptor but does not activate it.
- Eg. atropine, antagonist for muscarinic GPCRs, competes with acetylcholine.

2. Competitive antagonists:
- Compete with agonists for the same receptor binding site.
- Can be irreversible or reversible.
- Reversible = agonist can outcompete antagonist.
- Irreversible = agonist cannot replace antagonist, suppressed response.

3. C.A (reversible):
- Reversible = increasing antagonist concentration can outcompete antagonist.

4. Emax + EC50 of reversible antagonists:

 - Shift to the right, need more agonist to displace the agonist.
- Increasing conc of antagonist =
i) Emax = same, increasing [agonist] can displace antagonist.
ii) EC50 = increases, need more [agonist] to produce the same response.

5. C.A (irreversible):
- Irreversible = antagonist permanently binds to receptor; no amount of agonist will dislodge it.

6. Emax + EC50 of irreversible antagonists:

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 - Reduced response, suppression of cruve.
- Less receptors available, amount needed to produce a defined response = increased.
- Increasing conc of antagonist =
iii) Emax of agonist A reduces.
iv) EC50 of agonist A gets larger.

7. Measuring antagonism (Schild plot + pA2):

- Higher the number, more potent the antagonist.
- Same pA2 = acts through same receptor.

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 - Straight line = competitive antagonism.
- Curved line = non-competitive antagonist.

8. What determines a response?

- Affinity = how well a drug binds to a receptor.

- Efficacy = how well a drug activates a receptor.
- Combination of these determines outcome of response.

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9. How do allosteric modulators affect response?
- Binds to site on receptor distinct from agonist.
- Modulates affinity and efficacy.
- Can activate receptor independently in some contexts.
Orthostatic site = place on receptor where traditional agonist binds.
Allosteric site = other drugs/molecules can bind to other sites on receptor to modify effects of agonist.

10. Response curves for allosteric modulators:

- Affinity = affects EC50.
Positive = moves to left.
Negative = moves to the right.

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- Efficacy = affects Emax.
Positive = moves up.
Negative = moves down.