title: Structure-activity relationships comparing N-(6-methylpyridin-yl)-substituted aryl amides to 2-methyl-6-(substituted-arylethynyl)pyridines or 2-methyl-4-(substituted-arylethynyl)thiazoles as novel metabotropic glutamate receptor subtype 5 antagonists.
abstract: The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in anxiety, depression, pain, mental retardation, and addiction. The potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1) has been a critically important tool used to further elucidate the role of mGluR5 in these CNS disorders. In an effort to provide novel and structurally diverse selective mGluR5 antagonists, we previously described a set of analogues with moderate activity wherein the alkyne bond was replaced with an amide group. In the present report, extended series of both amide and alkyne-based ligands were synthesized. MGluR5 binding and functional data were obtained that identified (1) several novel alkynes with comparable affinities to 1 at mGluR5 (e.g., 10 and 20-23), but (2) most structural variations to the amide template were not well tolerated, although a few potent amides were discovered (e.g., 55 and 56). Several of these novel analogues show drug-like physical properties (e.g., cLogP range = 2-5) that support their use for in vivo investigation into the role of mGluR5 in CNS disorders.
authors.affiliation: Medicinal Chemistry Section, National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Santosh S
authors.initials: SS
authors.lastname: Kulkarni
authors.forename: Mu-Fa
authors.initials: MF
authors.lastname: Zou
authors.forename: Jianjing
authors.initials: J
authors.lastname: Cao
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000480:Alkynes; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles