Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders

G protein-coupled receptors (GPCRs) are highly successful drug targets, particularly for central nervous system (CNS) disorders. Compared to traditional drugs that target the orthosteric ligand-binding site of GPCRs, allosteric modulators have the potential to achieve greater subtype selectivity and allow the normal function of endogenous ligands to be preserved. Conn and colleagues reflect on the key principles for successful optimization of GPCR allosteric modulators. Novel allosteric modulators of G protein-coupled receptors (GPCRs) are providing fundamental advances in the development of GPCR ligands with high subtype selectivity and novel modes of efficacy that have not been possible with traditional approaches. As new allosteric modulators are advancing as drug candidates, we are developing an increased understanding of the major advantages and broad range of activities that can be achieved with these agents through selective modulation of specific signalling pathways, differential effects on GPCR homodimers versus heterodimers, and other properties. This understanding creates exciting opportunities, as well as unique challenges, in the optimization of novel therapeutic agents for disorders of the central nervous system.