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

By P. Conn, Arthur Christopoulos, Craig Lindsley. Nature reviews. Drug discovery, 2009

1,046 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/71d9ffb5ddeebb925654e480dfe9379b488c5c99

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In Cellular and Molecular Neuroscience

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Citations in the corpus

A Structural Framework for GPCR Chemogenomics: What's In a Residue Number? (2018, background): “domains involved in protein-protein interactions or ligand binding, whereas the transmembrane domain may be targeted by allosteric modulators in these receptors [44, 45].”
Computational Methods in Drug Discovery (2014, background): “This receptor has been implicated in neurologic disorders including anxiety, Parkinson’s disease, and schizophrenia (Gasparini et al., 2008; Conn et al., 2009).”
How were new medicines discovered? (2011, background): “Allosteric inhibition and activation are important for the pharmacological modulation of many receptors and channel”
Pathway and mechanism of drug binding to G-protein-coupled receptors (2011, background): “Allosteric GPCR modulators, which bind at sites distinct from the classical orthosteric binding pocket, hold the promise of enhanced selectivity compared to orthosteric GPCR drugs (33).”
The structure and function of G-protein-coupled receptors (2009, background): “This high conservation in the ligand-binding pocket is also observed in other subfamilies of GPCRs (such as dopamine, serotonin and histamine), and probably explains some of the difficulty in obtaining potent subtype-selective compounds in pharmaceutical discovery program”
Mutations causing syndromic autism define an axis of synaptic pathophysiology (2011, background): “PAMs are compounds that do not activate mGluR5 directly but act on an allosteric site to potentiate physiological activation of the recepto”
Ligand binding assays at equilibrium: validation and interpretation (2010, background): “Allosteric interplay between synthetic ligands and the orthosteric transmitter binding sites on receptors is a rich source of novel leads for drug development (Conn et al., 2009).”
Molecular dynamics simulation for all (2018, neutral): “Such drugs are greatly sought after because they offer the potential to increase selectivity between closely related receptor subtypes, modulate the body’s natural signaling patterns, and achieve efficacy at targets otherwise deemed undruggable (Conn et al., 2009).”
Drugs for allosteric sites on receptors. (2014, background): “In addition to PAMs and NAMs, silent allosteric modulators (SAMs; also known as neutral allosteric ligands) bind at allosteric sites and can block the activity of PAMs and NAMs, yet they have no effect on orthosteric ligand responses (1-14).”
International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update (2011, background): “Thus, the action of a PAM is expected to be more tissue-specific than the action of a stable, exogenously administered orthosteric agonist, which would circulate throughout the body (Conn et al., 2009).”