Allosteric Theory: Taking Therapeutic Advantage of the Malleable Nature of GPCRs

Abstract

The description of the allosteric modification of receptors to affect changes in their function requires a model that considers the effect of the modulator on both agonist affinity and efficacy. A model is presented which describes changes in affinity terms of the constant α (ratio of affinity in the presence vs the absence of modulator)and also the constant ξ (ratio of intrinsic efficacy of the agonist in the presence vs absence of modulator). This allows independent effects of both affinity and efficacy and allows the modeling of any change in thedose-response curve to an agonist after treatment with modulator. Examples are given where this type of model can predict effects of modulators that reduce efficacy but actually increase affinity of agonist (i.e. ifenprodil) and also of modulators that block the action of some agonists (the CXCR4 agonist SDF-1α by the antagonist AMD3 100) but not others for the same receptor (SDf-1α peptide fragments RSVM and ASLW). © 2007 Bentham Science Publishers Ltd.