- Partial inverse agonists: These agonists decrease the activity of constitutively active
receptors but not to their inactive state. - Protean agonists: These agonists acting on receptors possessing constitutive activity
display any response ranging from full agonism to full inverse agonism depending on
the level of constitutive activity in the system and the relative efficacies of the
constitutive activity and that induced by the agonist. - Biased agonists: This form of agonist behaviour is found with receptors that
can couple to two or more different G-proteins and as a consequence the agonist
preferentially selects one of them thus favouring one specific transduction
pathway. - Antagonists: In the absence of agonists these ligands produce no change in the
activity of the receptors. Three subclasses have been identified using the antagonist
in the presence of an agonist and using receptors not possessing constitutive
activity:
(i)Competitive reversible antagonists: The antagonist competes with the agonist for
the orthosteric sites so that the effect of the antagonist can be overcome by
increasing the concentration of agonist (Fig. 17.2).
(ii)Non-competitive reversible antagonists: The antagonist binds at a different site on
the receptors to that of the orthosteric site so that the effect of the antagonist
cannot be overcome by increasing the concentration of agonist.
(iii)Irreversible competitive antagonists: The antagonist competes with the agonist
for the orthosteric site but the antagonist forms a covalent bond with the site
so that its effect cannot be overcome by increasing the concentration of agonist. - Allosteric modulators: These bind to a site distinct from that of the orthosteric site and
can only be detected using functional, as opposed to ligand-binding, assays. They are
discussed more fully in Section 17.2.3.
As a result of this classification, ligand action on receptors can be characterised by a
number of parameters: - Intrinsic activity: This is a measure of the ability of an agonist to induce a response by
the receptors. It is defined as the maximum response to the test agonist relative to the
maximum response to a full agonist acting on the same receptors. All full agonists, by
definition, have an intrinsic activity of 1 whereas partial agonists have an intrinsic
activity of less than 1. - Efficacy (e): This is a measure of the inherent ability of an agonist to initiate a
physiological response following binding to the orthosteric site. The initiation of a
response is linked to the ability of the agonist to promote the formation of the active
conformation of the receptors whereas for inverse agonists it is linked to their ability
to promote the formation of the inactive conformation. While all full agonists must
have a high efficacy their efficacy values will not necessarily be equal, in fact values
ofehave no theoretical maximum value. Partial agonists have a low efficacy,
antagonists have zero efficacy and inverse agonists have negative efficacy. - Collateral efficacy: This relates to the ability of the agonist to preferentially select
one of the two or more possible transduction pathways displayed by the binding
665 17.2 Quantitative aspects of receptor–ligand binding