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

• X-ray structures of the transmembrane domains of mGlu1 and mGlu5 have been solved.
• These explain the difficulties encountered in developing allosteric modulator drugs.
• The mechanisms underlying mGlu5 pharmacological mode switching are revealed.
• Structure based approaches to drug discovery can now be applied to class C GPCRs.

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.

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