title: Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications.
abstract: Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Iso
authors.forename: Ewa
authors.initials: E
authors.lastname: Grajkowska
authors.forename: Jarda T
authors.initials: JT
authors.lastname: Wroblewski
authors.forename: Jared
authors.initials: J
authors.lastname: Davis
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Goeders
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Sanker
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Werner
authors.initials: W
authors.lastname: Tueckmantel
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000495:Allosteric Site; D000818:Animals; D002460:Cell Line; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000517:prevention & control*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008297:Male; D009294:Narcotics / Q000008:administration & dosage; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012646:Self Administration; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D008024:Ligands; D009294:Narcotics; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D003042:Cocaine