title: A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models.
abstract: We found that 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). In Chinese hamster ovary cells expressing human mGluR5, CDPPB potentiated threshold responses to glutamate in fluorometric Ca2+ assays more than 7-fold with an EC50 value of approximately 27 nM. At 1 microM, CDPPB shifted mGluR5 agonist concentration response curves to glutamate, quisqualate, and (R,S)-3,5-dihydroxyphenylglycine 3- to 9-fold to the left. At higher concentrations, CDPPB exhibited agonist-like activity on cells expressing mGluR5. No other activity was observed on any other mGluR or cell type at concentrations up to 10 microM. CDPPB had no effect on [3H]quisqualate binding to mGluR5 but did compete for binding of [3H]methoxyPEPy, an analog of the selective mGluR5 negative allosteric modulator MPEP. CDPPB was found to be brain penetrant and reversed amphetamine-induced locomotor activity and amphetamine-induced deficits in prepulse inhibition in rats, two models sensitive to antipsychotic drug treatment. These results demonstrate that positive allosteric modulation of mGluR5 produces behavioral effects, suggesting that such modulation serves as a viable approach to increasing mGluR5 activity in vivo. These effects are consistent with the hypothesis that allosteric potentiation of mGluR5 may provide a novel approach for development of antipsychotic agents.
authors.affiliation: Neuroscience-West Point, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Gene G
authors.initials: GG
authors.lastname: Kinney
authors.forename: Julie A
authors.initials: JA
authors.lastname: O'Brien
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.forename: Maryann
authors.initials: M
authors.lastname: Burno
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Bickel
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Clements
authors.forename: Tsing-Bau
authors.initials: TB
authors.lastname: Chen
authors.forename: David D
authors.initials: DD
authors.lastname: Wisnoski
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Philip R
authors.initials: PR
authors.lastname: Tiller
authors.forename: Sheri
authors.initials: S
authors.lastname: Smith
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Jacobson
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006224:Cricetinae; D004285:Dogs; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D000882:Haplorhini; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D015233:Models, Statistical; D009043:Motor Activity / Q000187:drug effects; D010797:Phthalimides / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000596:Amino Acids; D014150:Antipsychotic Agents; D001549:Benzamides; D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; C114624:LY 341495; C481448:N-(4-chloro-2-((1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl)phenyl)-2-hydroxybenzamide; D010797:Phthalimides; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; D000661:Amphetamine