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

Nature Reviews Drug Discovery volume 13, pages 692–708 (2014)Cite this article

Subjects

Key Points

  • Positive and negative allosteric modulators (PAMs and NAMs) have now been identified for members of each major subfamily of G protein-coupled receptors (GPCRs). Multiple allosteric modulators have been optimized to have drug-like properties, and several allosteric modulators of class A and class C GPCRs are now advancing in preclinical and clinical development.

  • The crystal structures of GPCRs bound to allosteric modulators are providing important new insights into the structural determinants of allosteric-modulator action. This new structural information reveals interesting similarities between the binding pocket for allosteric modulators of class C GPCRs and the orthosteric binding pocket of class A GPCRs.

  • Potential advantages of allosteric modulators that were theoretical are now gaining direct experimental support. For instance, there are now clear examples of the major advantages of using GPCR PAMs as opposed to orthosteric agonists in maintaining spatial and temporal aspects of GPCR signalling.

  • Stimulus bias can complicate the optimization of GPCR allosteric modulators for disorders of the central nervous system, in which the most appropriate signalling pathways are not known. However, there are also examples where the optimization of allosteric modulators that confer stimulus bias to GPCR signalling may be important for developing optimal clinical-development candidates.

  • Examples are now beginning to emerge in which allosteric modulators can differentiate between homomeric and heteromeric forms of class C GPCRs. Allosteric modulators that can differentiate between homomeric and heteromeric GPCRs can have highly specific effects in certain brain circuits.

  • After a decade of focused efforts on the optimization of allosteric modulators of GPCRs as drug candidates, principles are now emerging that are important for the successful lead optimization of candidate allosteric modulators.

Abstract

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.

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Figure 1: Structure of GPCRs in complex with allosteric modulators.
Figure 2: Heterointeractions between mGluR subunits differentially alter the pharmacology of allosteric modulators.
Figure 3: 'Molecular switches' within GPCR allosteric ligands.
Figure 4: 'Flat' SARs.
Figure 5: An approach for the chemical optimization of allosteric modulators.

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Acknowledgements

The authors acknowledge the following grant support: US National Institutes of Health (NIH) grants U01 MH087956, R01 MH062646, R01 MH073676, U19 MH097056, R01 NS031373, P50 NS071669 (to P.J.C.); R01 DA023947, R01 MH082867, U54 MH084659, U19 MH097056 (to C.W.L.); NIH grants R01 GM080403, R01 MH090192, R01 GM099842, R01 DK097376) and NSF grants BIO Career 0742762 and CHE 1305874 (to J.M.); NIH grant R21 NS078262, a Basic Research Grant from the International Rett Syndrome Foundation, and a Treatment Award from Autism Speaks (to C.M.N). Vanderbilt Specialized Chemistry Center is in the Molecular Libraries Probe Centers Network.

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  1. Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, 1215D LH, Tennessee, USA

    P. Jeffrey Conn, Craig W. Lindsley & Colleen M. Niswender

  2. Department of Chemistry, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Jens Meiler

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Correspondence to P. Jeffrey Conn.

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Competing interests

P.J.C., C.W.L. and C.M.N. receive research support from Bristol-Myers Squibb and AstraZeneca. Each of these three authors is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators and have been licensed by Vanderbilt University to AstraZeneca, Bristol-Myers Squibb, and Johnson & Johnson. C.W.L. has consulted for AbbVie and received compensation. Over the past 2 years, P.J.C. has consulted for and received compensation from Pfizer, Cambridge, Massachusetts, USA.

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Reported allosteric modulators of family A G protein-coupled receptors (PDF 204 kb)

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Reported allosteric modulators of family B G-protein-coupled receptors (PDF 148 kb)

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Reported allosteric modulators of family C G-protein-coupled receptors (PDF 228 kb)

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Cooperativity factors

Parameters that are used to quantify the magnitude of the effect of an allosteric ligand on the affinity or functional response to the orthosteric ligand.

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Conn, P., Lindsley, C., Meiler, J. et al. Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov 13, 692–708 (2014). https://doi.org/10.1038/nrd4308

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