Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia

Abstract

Background: Normalization of excessive glutamate neurotransmission through activation of the metabotropic glutamate receptor 2 (mGluR2) represents a novel and promising approach for the treatment of schizophrenia. This strategy has gained support through the evaluation of dual mGluR2/3 agonists that act directly at the glutamate (orthosteric) binding site. Importantly, clinical validation of the mechanism was achieved in a Phase II study in schizophrenia patients with mGluR2/3 agonist LY404039. Selective positive allosteric modulators (potentiators) of mGluR2 that bind to the transmembrane region of the receptor have shown efficacy in rodent models predictive of antipsychotic activity, but have yet to be evaluated in the clinic. Allosteric mGluR2 potentiators may offer advantages over orthosteric mGluR2/3 agonists as a result of their unique mode of action and ability to achieve superior mGluR2 selectivity. Objective/method: This review focuses on the structures and biological activities of small molecule potentiators of mGluR2 that appeared in the patent literature between 2006 and early 2009. Conclusion: Potent mGluR2 potentiators that span a broad range of structural diversity have been disclosed. Narrow patent filings within select series and drug-like properties of corresponding preferred compounds suggest that development candidates have likely been nominated.

Keywords::

• metabotropic glutamate receptor 2
• positive allosteric modulator
• potentiator
• schizophrenia