Metabotropic glutamate receptor 5-negative allosteric modulators for the treatment of psychiatric and neurological disorders (2009-July 2013)

Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) have been actively pursued for over a decade as a potential treatment for anxiety, depression, substance abuse, pain, levodopa-induced dyskinesia in Parkinson's disease, fragile X Syndrome, autism, gastroesophageal reflux disease and lower-urinary-tract disorders. This article begins with an introduction of preclinical validation of potential therapies for psychiatric and neurological disorders, and of clinical results, followed by a comprehensive overview of the mGlu5-negative allosteric modulator patent applications published between 2009 and July 2013, with a focus on the ana-lysis of structure and in silico CNS drug-like properties of example compounds and disclosed data. Given positive results in proof-ofconcept studies in humans for certain indications such as levodopa-induced dyskinesia in Parkinson's disease, fragile X Syndrome, gastroesophageal reflux disease, migraine and anxiety, and the soaring chemical diversity among the mGlu5-negative allosteric modulators, there is reason to believe that a drug will emerge from this therapeutic class in the near future.