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

Abstract

Tremendous advances have been made in the discovery of novel ligands for G-protein-coupled receptors (GPCRs) that act at allosteric sites to regulate receptor function. Small molecules can act at allosteric sites to directly activate the receptor (allosteric agonists) or to potentiate (positive allosteric modulators) or inhibit (negative allosteric modulators) responses to traditional GPCR agonists that act at the orthosteric site. Allosteric modulators of GPCRs often provide higher selectivity for individual GPCR subtypes than has been achieved with traditional orthosteric-site ligands. Allosteric ligands can provide novel modes of efficacy that are not possible with orthosteric-site ligands and may provide advantages as therapeutic agents, such as allosteric potentiator and partial antagonist activity. Two allosteric modulators that are not marketed for treatment of human disorders and multiple allosteric modulators are now advancing in discovery and clinical development programmes. Allosteric modulators may lead to novel therapeutic agents for treatment of multiple psychiatric and neurological disorders, including anxiety disorders, schizophrenia and Alzheimer's disease.