title: Synthesis and receptor assay of aromatic-ethynyl-aromatic derivatives with potent mGluR5 antagonist activity.
abstract: Noncompetitive antagonists of the human metabotropic glutamate receptor subtype 5 (mGluR5) have been implicated as potential therapeutics for the treatment of a variety of nervous system disorders, including pain, anxiety, and drug addiction. To discover novel noncompetitive antagonists to the mGluR5, we initiated an SAR study around the known lead compounds MPEP and M-MPEP. Our results pointed out the critical role of the para position of the two aromatic rings, which leads to inactive products and permitted the discovery of potent mGluR5 antagonists (e.g., 16, 25, 28, 34 IC(50) = 13.5, 11.9, 21, 15 nM, respectively).
authors.affiliation: Department of Psychiatry, Yale University and VA Connecticut/116A2, 950 Campbell Avenue, West Haven, CT 06516, USA.
authors.forename: David
authors.initials: D
authors.lastname: Alagille
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Baldwin
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Jarda T
authors.initials: JT
authors.lastname: Wroblewski
authors.forename: Ewa
authors.initials: E
authors.lastname: Grajkowska
authors.forename: Gilles D
authors.initials: GD
authors.lastname: Tamagnan
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D000242:Cyclic AMP