Agonists, antagonists, and partial agonists

Receptor ligands can be distinguished on the basis of their potential to initiate a biological response following receptor binding:

• Agonists bind to a receptor protein to produce a conformational change, which is necessary to initiate a signal that is coupled to a biological response. As the free ligand concentration increases, so does the proportion of receptors occupied, and hence the biological effect. When all of the receptors are occupied the maximum biological effect is achieved. It has been observed in many receptor systems that full agonists can elicit the maximum effect without occupying all available receptors, suggesting the concept of ‘spare receptors’. This apparent excess of receptors allows full responses to occur at lower ligand concentrations than would otherwise be required.

• Antagonists bind to a receptor but do not produce the conformational change that initiates an intracellular signal. Occupation of the receptor by a competitive antagonist prevents binding of other ligand and so 'antagonizes' the biological response to the agonist. The inhibition that antagonists produce can be overcome by increasing the dose of the agonist. Some antagonists interfere with the response to the agonist in other ways than receptor competition and are known as non-competitive antagonists. Simply increasing the dose of the agonist cannot overcome their effects and so the maximum response to the agonist (its 'efficacy') is reduced.

• Partial agonists are able to activate a receptor but cannot produce a maximal signaling effect equivalent to that of a full agonist even when all available receptors are occupied. When mixed with full agonists, partial agonists block receptor sites that could potentially be occupied by the full agonist, which reduces the overall response (i.e. they seem to antagonize the effect of the full agonist). Partial agonists have some advantages as therapeutic agents. Although they are unable to achieve the same maximum effect as the full agonist, they are less likely to produce receptor-mediated adverse effects at the top of their dose–response curve (e.g. the partial opioid receptor agonist buprenorphine does not cause as much respiratory depression as morphine when it is used as an analgesic).

• Inverse agonists produce the opposite effect to the full agonist when they bind to a receptor. For inverse agonists to be identified, the relevant endogenous receptor must show some degree of coupling to a biological response even in the absence of ligand binding (i.e. constitutive activity). Many receptors possess constitutive activity.