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

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Jeffrey Conn, P., Christopoulos, Arthur, Lindsley, Craig W.·2009·Nature Reviews Drug Discovery

DOI 10.1038/nrd2760PMC PMC2907734

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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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Authors: Jeffrey Conn, P., Christopoulos, A., & Lindsley, C. W.
Affiliations: Monash University (AU)
Vanderbilt University (US)
ORCID: Christopoulos, Arthur
Lindsley, Craig W.
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2009-01
Volume: 8
Issue: 1
Pages: 41-54
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd2760
PMC: PMC2907734
OpenAlex: W2003736358
Cited by: 1,063
References: 139
Citations by year: 2026: 30 · 2025: 46 · 2024: 37 · 2023: 25 · 2022: 48 · 2021: 51 · 2020: 44 · 2019: 58 · 2018: 57 · 2017: 68 · 2016: 64 · 2015: 67 · 2014: 69 · 2013: 80 · 2012: 75
FWCI: 6.60
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Mental Health (R01MH073676, R01MH074953, R01MH062646)
National Institute on Drug Abuse (R01DA023926)
National Institute of Neurological Disorders and Stroke (R01NS031373)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: G protein-coupled receptors, allosteric modulators, allosteric site, orthosteric ligands, mental illness, neurological disorders, CNS drug discovery, receptor selectivity, novel therapeutic agents
MeSH terms: Allosteric Regulation, Animals, Central Nervous System Diseases, Drug Evaluation, Preclinical, Humans, Ligands, Drug Design, Receptors, G-Protein-Coupled

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

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