Agonists and Antagonists: Definition, Mechanism and Types

Agonists and Antagonists

In pharmacology, agonists and antagonists are terms used to describe the effects of drugs on biological receptors. Agonists activate receptors, mimicking the action of endogenous compounds, while antagonists block or inhibit receptor activation. This comprehensive exploration will explore the mechanisms, types, and examples of agonists and antagonists, including competitive and noncompetitive antagonists.

What are Agonists?

Agonists are drugs or endogenous substances that bind to and activate a receptor, eliciting a biological response. They can either mimic the effects of endogenous ligands or enhance their activity.

Mechanism of Action

Agonists bind to receptors with affinity, inducing a conformational change that activates the receptor. This activation triggers downstream cellular responses, leading to the observed physiological effects.

Types of Agonists:

Full Agonist – A substance that binds to a receptor and fully activates it, producing the maximum possible biological response. Full agonists have high intrinsic activity (efficacy) and can mimic the action of endogenous ligands.

Example: Morphine, which fully activates opioid receptors to produce analgesic effects.

Partial Agonist – A substance that binds to a receptor and activates it, but produces a weaker (submaximal) biological response compared to a full agonist, even at full receptor occupancy. Partial agonists have lower intrinsic activity and can act as antagonists in the presence of a full agonist by competing for receptor binding.

Example: Buprenorphine, which partially activates opioid receptors but has a ceiling effect on respiratory depression.

Inverse Agonist – A substance that binds to a receptor and induces a response opposite to that of a full agonist, decreasing the receptor’s basal (constitutive) activity. Inverse agonists can only act on receptors that exhibit intrinsic activity in the absence of a ligand.

Example: Beta-carbolines, which act as inverse agonists at GABA-A receptors, leading to increased anxiety and convulsions.

Super Agonist – A substance that binds to a receptor and produces a response greater than that of the natural (endogenous) ligand, leading to an exaggerated physiological effect. Super agonists have higher efficacy than the endogenous ligand.

Example: Some synthetic peptides that activate hormone receptors more strongly than natural hormones.

Biased Agonist – A substance that binds to a receptor and preferentially activates specific signaling pathways over others, leading to selective therapeutic effects while minimizing side effects. This concept is important in drug development to enhance efficacy and safety.

Example: TRV130 (oliceridine), a biased agonist at the opioid receptor that selectively activates pain-relief pathways while reducing respiratory depression.

Antagonists (Competitive Antagonists and Noncompetitive Antagonists)

Antagonists are substances that bind to receptors without activating them, preventing the binding of agonists and inhibiting receptor activation. They can be competitive or noncompetitive.

Mechanism of Action

Antagonists competitively or noncompetitively bind to receptors, blocking the binding site or inhibiting the downstream signalling pathways, thus preventing the effects of agonists.

Competitive Antagonists

Competitive antagonists compete with agonists for the same binding site on a receptor. They can be overcome by increasing the concentration of the agonist.

Mechanism of Action

Competitive antagonists bind reversibly to the same site as the agonist, preventing the agonist from binding and activating the receptor.

Example: Flumazenil (GABAA Receptor Competitive Antagonist):

  Mechanism: Binds to the benzodiazepine binding site on the GABAA receptor.

  Effects: Reverses the sedative effects of benzodiazepines by competitively blocking their action.

Noncompetitive Antagonists

Noncompetitive antagonists bind to a site on the receptor distinct from the agonist-binding site. Their binding results in a conformational change that makes the receptor less responsive to agonists.

Mechanism of Action:

Noncompetitive antagonists bind irreversibly or with high affinity, inhibiting the receptor’s function even in the presence of high concentrations of agonists.

Example: Phenoxybenzamine (Alpha-Adrenergic Receptor Noncompetitive Antagonist):

  Mechanism: Irreversibly blocks alpha-adrenergic receptors.

  Effects: Used to treat conditions like pheochromocytoma (a rare tumour that forms in the adrenal gland) by inhibiting the vasoconstrictive effects of catecholamines.

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