Agonists and Antagonists

Study Notes

Agonists and antagonists are crucial concepts in pharmacology and physiology, relating to how drugs and endogenous molecules interact with receptors in the body.
Receptors are proteins on cell surfaces or within cells that bind to specific molecules, triggering a cellular response.

Agonists are molecules (drugs, neurotransmitters, hormones) that bind to a receptor and activate it, producing a biological response.
They have both affinity and efficacy.
Affinity refers to the ability of a molecule to bind to a receptor.
Efficacy refers to the ability of the molecule, once bound, to activate the receptor and produce a response.
Agonists can be classified based on the magnitude of the response they produce: full agonists, partial agonists, and inverse agonists.

Full agonists produce the maximal possible response for that receptor in the system.
They stabilize the receptor in its active state.
Example: Morphine is a full agonist at the μ-opioid receptor, producing a strong analgesic effect.

Partial agonists do not produce the maximal response, even when all receptors are occupied.
They have efficacy lower than that of a full agonist.
They may also act as antagonists in the presence of a full agonist by competing for receptor binding.
Example: Buprenorphine is a partial agonist at the μ-opioid receptor; it provides analgesia but with a lower risk of respiratory depression compared to morphine.

Inverse agonists bind to a receptor and produce an effect opposite to that of a typical agonist.
They stabilize the receptor in its inactive state, reducing any baseline activity the receptor might have.
Example: Some antihistamines act as inverse agonists at histamine receptors, reducing histamine activity and alleviating allergy symptoms.

Antagonists are molecules that bind to a receptor but do not activate it.
They block the receptor, preventing agonists (endogenous or exogenous) from binding and exerting their effects.
They have affinity but lack efficacy.
Antagonists are classified based on their binding properties: competitive, non-competitive, and irreversible.

Competitive antagonists bind reversibly to the same site as the agonist.
They compete with the agonist for receptor binding.
The effect of a competitive antagonist can be overcome by increasing the concentration of the agonist.
This shifts the agonist dose-response curve to the right, increasing the EC50 (the concentration of agonist required to achieve 50% of the maximal response) but not affecting the maximal response.
Example: Naloxone is a competitive antagonist at opioid receptors, used to reverse opioid overdose.

Non-competitive antagonists bind to a site different from the agonist binding site (allosteric site) or bind irreversibly to the same site.
They reduce the maximal response that the agonist can achieve, regardless of the agonist concentration.
They can decrease the receptor's affinity for the agonist or prevent the receptor from being activated.
The agonist dose-response curve is shifted downward, reducing the maximal effect (Emax).
Example: Ketamine at the NMDA receptor.

Irreversible antagonists bind permanently to the receptor, either to the active site or to an allosteric site.
They form a stable, permanent bond (usually covalent), effectively reducing the number of receptors available for activation by the agonist.
The effect is similar to that of non-competitive antagonists, reducing the maximal response of the agonist.
The only way to overcome the effect of an irreversible antagonist is to synthesize new receptors.
Example: Phenoxybenzamine, which binds irreversibly to α-adrenergic receptors