mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease.
Although Parkinson's disease was first diagnosed nearly 200 years ago, its effective treatment still remains elusive for most of those diagnosed. The gold standard of treatment for most patients is 3,4-dihydroxy-L-phenylalanine. This drug works for most individuals early in the disease; however, resistant symptoms start to emerge after several years of treatment. There has been increased interest in finding novel therapies to help Parkinson's disease patients. Such strategies may have the benefit of not only treating the symptomatic issues of the disorder, but might also offer promise in protecting dopaminergic neurons from further degeneration. One such target that is now receiving much attention from the scientific community is the metabotropic glutamate receptor mGluR4. In this article, we briefly review Parkinson's disease and then recent work in the mGluR area, with a focus on the efforts being made toward finding and optimizing novel mGluR4 positive allosteric modulators (PAMs). Preclinically in rodent models, mGluR4 activation has offered much promise as a novel treatment of Parkinson's disease. Additionally, the specific use of PAMs, rather than direct-acting agonists at the orthosteric glutamate site, continues to be validated as a viable treatment option for this target. It is anticipated that continued progress in this area will further our understanding of the potential of mGluR4 modulation as a novel symptomatic and potentially disease-modifying treatment for Parkinson's disease.
Hopkins
Corey R
CR
Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232-36000, USA. corey.r.hopkins@vanderbilt.edu
Lindsley
Craig W
CW
Niswender
Colleen M
CM
D000494:Allosteric Regulation; D001578:Benzopyrans / Q000737:chemistry / Q000627:therapeutic use; D005971:Glutamates / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy*; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology
D001578:Benzopyrans; D005971:Glutamates; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D018094:Receptors, Metabotropic Glutamate; C108823:metabotropic glutamate receptor 4