they have several distinct conformational states and that these states can be switched
with distinct kinetics by the various classes of agonist.
As previously pointed out, the pharmaceutical industry seeks to identify receptor
agonists or antagonists that can be used for the treatment of specific clinical conditions.
The potential role of inverse agonists in this respect remains to be fully evaluated.
However, it is apparent that clinical conditions caused by a mutant receptor that has
constitutive activity in contrast to the normal receptor that is only active in the presence
of the physiological agonist could be treated with an inverse agonist that would eliminate
the constitutive activity. Equally, use ofan inverse agonist may be advantageous in
conditions resulting from the overstimulation of the receptor due to the overproduction
of the signalling agonist. At the present time many inverse agonists are used clinically
althoughatthetimeoftheirdevelopmenttheywerebelievedtobecompetitiveantagonists.17.2.3 Allosteric modulators
Studies using functional screening assays have demonstrated that many receptors
possessallosteric sitesdistinct from the orthosteric agonist site. Such sites have been
identified in monomeric receptors as well as those that form homo- and heterodimers.
These allosteric sites are capable of bindingallosteric modulatorsthat exert one of
three distinct effects (Fig. 17.3):- alteration of the affinity of the agonist for its orthosteric site; or
- alteration of the efficacy (i.e. ability to produce the response of the receptor via its
various effectors) of the agonist; or - display an efficacy independent of the presence of an agonist. Such efficacy could be
of the agonist or inverse agonist variety.
The binding to the allosteric site is characterised by its dissociation constant and by a
cooperativity factora, which is a thermodynamic measure of the strength of interaction
between this site and the orthosteric site. Since these two sites are distinct, allosteric
modulators induce unique conformational changes in the receptor and at least in
principle these may alter the signalling, desensitisation and internalisation states induced
by agonists binding at the orthosteric site. Recently, evidence has been obtained to
indicate that allosteric interaction between distinct sites may operate by ligand-depend-
ent changes in the dynamic properties of the receptor rather than simple conformational
changes. This idea is based on the recognition that receptors, like enzymes, exist as
assemblies of conformations the balance between which can be altered by ligand binding
(Section 15.2.4). Ligands acting as allosteric modulators can be classified into one of four
types on the basis of the effects they produce on the activity of the orthosteric site:- Allosteric agonist: This is a ligand that binds to an allosteric site and mediates the
activation of the receptor in the absence of the physiological agonist. - Allosteric enhancer: This is a ligand that enhances the affinity or efficacy of an
agonist acting on the orthosteric site without having any activity of its own. - Allosteric modulator: This is a ligand that alters (increases or decreases) the activity of
an agonist or antagonist acting on the orthosteric site without having any activity of
670 Cell membrane receptors and cell signalling