Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors.
Metabotropic glutamate receptors (mGluRs) have been proposed as novel targets for the treatment of a variety of disorders. Recently, highly selective allosteric modulators of the mGluRs have been developed by several groups. These allosteric compounds provide an unprecedented degree of selectivity for individual mGluRs, allowing for more detailed functional studies on the roles of these receptors. Furthermore, the allosteric approach avoids many of the hurdles associated with the development of direct agonists as drugs, and provides a clear path forward for clinical proof-of-concept studies. Currently, both positive allosteric modulators of mGluR2 and negative allosteric modulators of mGluR5 hold promise as novel anxiolytics, and positive allosteric modulators of mGluR4 appear to be an exciting new target for the treatment of Parkinson's disease.
Marino
Michael J
MJ
Neuroscience Drug Discovery - Movement Disorders, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Conn
P Jeffrey
PJ
D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
D001578:Benzopyrans; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; D007093:Imidazoles; C476436:N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C108822:metabotropic glutamate receptor 2; C032794:fenobam; C121465:6-methyl-2-(phenylethynyl)pyridine; C108823:metabotropic glutamate receptor 4