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Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators. | LitMetric

Pharmacology, Signaling and Therapeutic Potential of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators.

ACS Pharmacol Transl Sci

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia.

Published: December 2024

AI Article Synopsis

Article Abstract

Metabotropic glutamate receptors are a family of eight class C G protein-coupled receptors regulating higher order brain functions including cognition and motion. Metabotropic glutamate receptors have thus been heavily investigated as potential drug targets for treating neurological disorders. Drug discovery efforts directed toward metabotropic glutamate receptor subtype 5 (mGlu) have been particularly fruitful, with a wealth of drug candidates and pharmacological tools identified. mGlu negative allosteric modulators (NAMs) are promising novel therapeutics for developmental, neuropsychiatric and neurodegenerative disorders (e.g., Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, autism spectrum disorders, substance use disorders, stroke, anxiety and depression) and show promise in ameliorating adverse effects induced by other medications (e.g., L-dopa induced dyskinesia in Parkinson's Disease). However, despite preclinical success, mGlu NAMs are yet to reach the market due to poor safety and efficacy profiles in clinical trials. Herein, we review the physiology and signal transduction of mGlu. We provide a comprehensive critique of therapeutic options with respect to mGlu5 inhibitors, spanning from orthosteric antagonists to NAMs. Finally, we address the challenges associated with drug development and highlight future directions to guide rational drug discovery of safe and effective novel therapeutics.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651194PMC
http://dx.doi.org/10.1021/acsptsci.4c00213DOI Listing

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