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

Nat Rev Drug Discov. 2014 Sep;13(9):692-708. doi: 10.1038/nrd4308.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • Central Nervous System Agents / chemistry
  • Central Nervous System Agents / metabolism
  • Central Nervous System Agents / therapeutic use*
  • Central Nervous System Diseases / drug therapy*
  • Central Nervous System Diseases / metabolism
  • Drug Discovery / methods
  • Drug Discovery / trends*
  • Humans
  • Receptors, G-Protein-Coupled / metabolism*
  • Treatment Outcome


  • Central Nervous System Agents
  • Receptors, G-Protein-Coupled