Allosteric interactions at GPCRs, whether mediated by small molecules or other proteins, can result in profound perturbations in ligand binding and GPCR function. Targeting small molecule allosteric sites on GPCRs holds much promise in the field of drug discovery. However, a continuing challenge to the field is the ability to detect, validate, and quantify allosteric ligand behaviors. In this respect, appropriately designed screening strategies are required to overcome potential confounding issues such as probe-dependence and differential modulation of affinity and efficacy. Regardless, compared to orthosteric sites, allosteric sites can accommodate a greater diversity of che-motypes and as such offer the potential for the development of therapeutics with greater subtype selectivity. For allosteric modulators, there is also the prospect of maintaining spatial and temporal aspects of GPCR function. Exploiting a bitopic binding mode is an alternative avenue for the development of selective agonists with high affinity, but perhaps also pathway-specific efficacy. Conversely, this approach could be used to develop highly selective antagonists and inverse agonists, thus contributing significantly to the pharmacologist's armamentarium and hopefully, to the clinician's therapeutic options.
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