Subtype-selective noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1).
This article describes recent advances in the development of subtype-selective, noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1). mGluR1 plays an important role in modulating synaptic transmission and neuronal excitability via intracellular signal transduction pathways and has been implicated in a number of CNS disorders. Allosteric modulation of mGluR1 by potentiation and antagonism occurs through binding to the seven transmembrane domain. In addition to blocking agonist-dependent responses, many of the antagonists also show inverse-agonist activity by blocking constitutive receptor activity. Highly potent and selective mGluR1 radioligands have been used to evaluate receptor binding in vivo and in vitro. Some of these novel agents have demonstrated high levels of CNS exposure and receptor occupancy in vivo, as well as efficacy in a number of preclinical models of neurological disorders.
Layton
Mark E
ME
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486 USA. mark-layton@merck.com
D000494:Allosteric Regulation; D000818:Animals; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1