Structures of mGluRs shed light on the challenges of drug development of allosteric modulators.

Kirstie A Bennett, Andrew S Doré, John A Christopher, Dahlia R Weiss, Fiona H Marshall

Journal: Current opinion in pharmacology 2015;20():1-7

PMID: 25462286

Full Text on Elsevier Science View on PubMed

Abstract

The metabotropic glutamate receptor family includes many potential therapeutic targets for a wide range of neurological disorders however to date no approved drugs have progressed to market. For some receptor subtypes it has been difficult to separate therapeutic benefit from undesirable side effects. For others finding suitable drug like molecules has been challenging. Chemotypes identified from screening have been limited and difficult to optimise away from undesirable groups. Frequently within related series, compounds have switched from agonist to antagonists. Recently the structures of the transmembrane domain of mGlu1 and mGlu5 have been solved revealing the binding site of allosteric modulators which provides an understanding of the difficulties to date and an opportunity for future structure based approaches to drug design.

Address: Heptares Therapeutics Ltd, Biopark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK.; Heptares Therapeutics Ltd, Biopark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK. Electronic address: [email protected].

DOI: 10.1016/j.coph.2014.09.022

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MeSH Terms: Allosteric Regulation, Binding Sites, Drug Design, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Humans, Molecular Targeted Therapy, Receptors, Metabotropic Glutamate