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

Key Points

  • 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.

Abstract

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.

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Figure 1: Modes of action of allosteric modulators.
Figure 2: Allosteric modulators of GPCR-associated signalling pathways.
Figure 3: Structures of the two marketed GPCR allosteric modulators.

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Correspondence to P. Jeffrey Conn.

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Dr Conn has received fees over the past 2 years as a consultant from: Merck and Co., Johnson and Johnson, Hoffman La Roche, Sepracor Inc., GlaxoSmithKline, Lundbeck Research USA, Epix Pharmaceuticals, Evotec Inc., Addex Pharmaceuticals, Seaside Therapeutics, AstraZeneca USA, NeurOp Inc., Forest Research Institute, Millipore Corp., Genentech and Otsuka. Dr Christopoulos has received fees as a consultant from: GlaxoSmithKline, Pfizer, Amgen, Bristol–Myers Squibb, Addex, Alchemia, Eli Lilly and Merck and Co. Dr Lindsley has received fees as a consultant from Amgen.

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Glossary

Orthosteric site

The binding site for the endogenous ligand on a receptor.

Allosteric modulator

A ligand that binds to an allosteric site and modulates the binding and/or signalling of an orthosteric ligand.

Allosteric site

A binding site on a receptor that is topographically distinct from the orthosteric site.

Cooperativity

The binding of two or more molecules of the same ligand to a receptor complex to initiate a response. Also used in a less strict sense to describe the allosteric interaction between more than one molecule of any chemical type on a receptor complex.

Stimulus-trafficking

The ability of a ligand to preferentially stabilize specific GPCR conformations, each associated with its own repertoire of stimuli and signalling behaviours, to the exclusion of other possible receptor states.

Allosteric agonist

A ligand that binds to an allosteric site and causes receptor activation (allosteric agonist) or reduces constitutive receptor activity (allosteric inverse agonist) in the absence of an orthosteric ligand.

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Jeffrey Conn, P., Christopoulos, A. & Lindsley, C. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8, 41–54 (2009). https://doi.org/10.1038/nrd2760

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