Metabotropic glutamate receptor 5-positive allosteric modulators for the treatment of schizophrenia (2004-2012)

The mGlu5, a class C G-protein-coupled receptor and member of the group I mGlu receptor family, has been demonstrated to play a role in a number of therapeutic areas within the CNS, including schizophrenia, dementia, epilepsy, cognition, drug abuse, and fragile X syndrome. Small-molecule modulation of mGlu5 via positive allosteric modulators (PAMs) is being pursued as a promising approach for the treatment of schizophrenia and has been validated preclinically in a number of animal models. This article provides a brief historical overview of mGlu5 PAMs in the primary literature followed by a comprehensive overview of the patent literature since 2004. Schizophrenia is a complex disorder and although no mGlu5 PAMs have progressed into clinical trials in patients, the target continues to show promise as an attractive non-dopaminergic therapy. The successful development of mGlu5 PAMs for clinical testing must address several issues, including challenges associated with 'molecular switches', allosteric-agonist activity and stimulus bias.