title: Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series.
abstract: We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.
authors.affiliation: Institute for Neurodegenerative Disorders, 60 Temple St., Suite 8A, New Haven, CT 06510, USA. dalagille@indd.org
authors.forename: David
authors.initials: D
authors.lastname: Alagille
authors.forename: Herve
authors.initials: H
authors.lastname: DaCosta
authors.forename: Yelin
authors.initials: Y
authors.lastname: Chen
authors.forename: Kamondanai
authors.initials: K
authors.lastname: Hemstapat
authors.forename: Alice
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Baldwin
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Conn
authors.forename: Gilles D
authors.initials: GD
authors.lastname: Tamagnan
mesh_terms: D000114:Acetylene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D008024:Ligands; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C044736:phenylacetylene; D000114:Acetylene