Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders

G protein–coupled receptors (GPCRs) represent one of the most targeted protein families in pharmaceutical research. Traditionally, drug discovery programmes have searched for ligands that act at endogenous orthosteric sites. Here, Conn and colleagues discuss recent advances in the identification of novel GPCR ligands that act at allosteric sites, highlighting their potential in the treatment of psychiatric and neurological disorders. Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.