title: Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines.
abstract: We describe the synthesis and SAR of a series of analogues of the mGlu(5) partial antagonist 5-(phenylethynyl)pyrimidine. New molecular switches are identified that modulate the pharmacological activity of the lead compound. Slight structural modifications around the proximal pyrimidine ring change activity of the partial antagonist lead to that of potent and selective full negative allosteric modulators and positive allosteric modulators, which demonstrate in vivo efficacy in rodent models for anxiolytic and antipsychotic activity, respectively.
authors.affiliation: Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Sharma
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kedrowski
authors.forename: Jerri M
authors.initials: JM
authors.lastname: Rook
authors.forename: Randy L
authors.initials: RL
authors.lastname: Smith
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Alice L
authors.initials: AL
authors.lastname: Rodriguez
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; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011743:Pyrimidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate