title: Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype.
abstract: This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhou
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Lindsley
authors.forename: Uyen
authors.initials: U
authors.lastname: Le
authors.forename: Mark D
authors.initials: MD
authors.lastname: Grier
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation; D055808:Drug Discovery; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C578935:GRM5 protein, human; D006575:Heterocyclic Compounds, 3-Ring; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate