Activation of Group II metabotropic glutamate receptors (mGluR2 and mGluR3) as a novel approach for treatment of schizophrenia

Abstract

In the last decade, many advances have suggested that activators of mGluR2 and/or mGluR3 may provide a novel approach for the treatment of schizophrenia. Preclinical and clinical studies with traditional orthosteric agonists nonselective for mGluR2 and mGluR3 have provided key studies demonstrating the viability of this approach. Recent advances in allosteric ligand development have led to the discovery of positive allosteric modulators (PAMs) selective for mGluR2, which have demonstrated efficacy in animal models predictive of antipsychotic activity. These mGluR2 PAMs, in conjunction with studies in mGluR2, mGluR3, and mGluR2/3 knockout mice, have suggested that mGluR2 may be the predominant receptor responsible for the antipsychotic efficacy of nonselective mGluR2/3 agonists. Recently, a heterocomplex between mGluR2 and the 5-HT2A serotonin receptor has been reported with functional consequences for both receptors, providing a novel target for therapeutic development. Together, these many advances have provided a strong foundation for the continued development of mGluR2/3 activators as a novel approach for the treatment of schizophrenia. © Springer Basel AG 2010.