Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

Craig W. Lindsley; Kyle A. Emmitte; Corey R. Hopkins; Thomas M. Bridges; Karen J. Gregory; Colleen M. Niswender; P. Jeffrey Conn

doi:10.1021/acs.chemrev.5b00656

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

Craig W. Lindsley, Kyle A. Emmitte, Corey R. Hopkins, Thomas M. Bridges, Karen J. Gregory, Colleen M. Niswender, P. Jeffrey Conn

Research output: Contribution to journal › Review article › peer-review

132 Scopus citations

Abstract

Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1-5 and 7 (mGlu_1-5,7) highlighting key concepts ("molecular switches", signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.

Original language	English (US)
Pages (from-to)	6707-6741
Number of pages	35
Journal	Chemical Reviews
Volume	116
Issue number	11
DOIs	https://doi.org/10.1021/acs.chemrev.5b00656
State	Published - Jun 8 2016
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)

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10.1021/acs.chemrev.5b00656

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title = "Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors",

abstract = "Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1-5 and 7 (mGlu1-5,7) highlighting key concepts ({"}molecular switches{"}, signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.",

author = "Lindsley, {Craig W.} and Emmitte, {Kyle A.} and Hopkins, {Corey R.} and Bridges, {Thomas M.} and Gregory, {Karen J.} and Niswender, {Colleen M.} and Conn, {P. Jeffrey}",

note = "Funding Information: The authors warmly acknowledge the NIH [(NIGMS, NIMH, NIDA): MH102548, U19MH106839, DA037207, GM106232, MH082867, DA023947, MH087965, MH097056, MH062646, MH074953 and MH08465]; Autism Speaks Treatment Award; and William K. Warren, Jr. (and the William K. Warren Foundation) for support of our programs in allosteric modulation of GPCRs. Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

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AU - Bridges, Thomas M.

AU - Gregory, Karen J.

AU - Niswender, Colleen M.

AU - Conn, P. Jeffrey

N1 - Funding Information: The authors warmly acknowledge the NIH [(NIGMS, NIMH, NIDA): MH102548, U19MH106839, DA037207, GM106232, MH082867, DA023947, MH087965, MH097056, MH062646, MH074953 and MH08465]; Autism Speaks Treatment Award; and William K. Warren, Jr. (and the William K. Warren Foundation) for support of our programs in allosteric modulation of GPCRs. Publisher Copyright: © 2016 American Chemical Society.

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Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

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