Metabotropic glutamate receptor 4 (mGlu_4)-positive allosteric modulators for the treatment of Parkinson's disease: historical perspective and review of the patent literature

摘要

Introduction: Metabotropic glutamate receptor 4 (mGlu_4) is a group III GPCR and has been demonstrated to play a major role in a number of therapeutic areas within the CNS. As the orthosteric site of all glutamate receptors is highly conserved, modulating mGlu_4 via allosteric modulation has emerged as a very attractive mode-of-action and has been validated preclinically in a number of animal models for Parkinson's disease, anxiety, pain, and neuroinflammation. Areas covered: In this review, the patent literature for mGlu_4-positive allosteric modulators over the past 4 years will be provided. Patents from all companies are discussed and an overview of the chemical matter and relevant biological properties will be given. Expert opinion: Although there has yet to be an mGlu_4-positive allosteric modulator progressed into clinical trials, there is a wealth of preclinical data from the primary literature that shows the promise of this emerging target. A number of academic and industry laboratories have recently published exciting patent data covering a multitude of chemical matter. Positive allosteric modulation of mGlu_4 remains one of the more attractive non-dopaminergic therapies for Parkinson's disease, as well as emerging data for other indications such as pain, neuroinflammation, schizophrenia and diabetes, which could potentially make mGlu_4 a significant therapeutic target going forward.