title: Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression.
abstract: There is growing evidence suggesting that antagonists of group II metabotropic glutamate receptors (mGluR2/3) exhibit antidepressant-like properties in several preclinical models of depression. However, all those studies have been performed using competitive group II non-selective orthosteric antagonists. In this study we extensively characterized a group II selective negative allosteric modulator (4-[3-(2,6-Dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one, namely RO4491533, Woltering et al., 2010) in several in vitro biochemical assays and in vivo models of depression. In vitro, RO4491533 completely blocked the glutamate-induced Ca(2+) mobilization and the glutamate-induced accumulation in [(35)S]GTP(γS) binding in cells expressing recombinant human or rat mGluR2 and in native tissues. Results from Schild plot experiments and reversibility test at the target on both cellular and membrane-based assays confirmed the negative allosteric modulator properties of the compound. RO4491533 was equipotent on mGluR2 and mGluR3 receptors but not active on any other mGluRs. RO4491533 has acceptable PK properties in mice and rats, is bioavailable following oral gavage (F = 30%) and brain-penetrant (CSF conc/total plasma conc ratio = 0.8%). RO4491533 appeared to engage the central mGluR2 and mGluR3 receptors since the compound reversed the hypolocomotor effect of an mGluR2/3 orthosteric agonist LY379268 in a target-specific manner, as did the group II orthosteric mGluR2/3 antagonist LY341495. RO4491533 and LY341495 dose-dependently reduced immobility time of C57Bl6/J mice in the forced swim test. Also, RO4491533 and LY341495 were active in the tail suspension test in a line of Helpless (H) mice, a putative genetic model of depression. These data suggest that mGluR2/3 receptors are viable targets for development of novel pharmacotherapies for depression.
authors.affiliation: Addex Pharma SA, Geneva, Switzerland. brice.campo@addexpharma.com
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambeng
authors.forename: M
authors.initials: M
authors.lastname: El Yacoubi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Royer-Urios
authors.forename: Manfred
authors.initials: M
authors.lastname: Schneider
authors.forename: Coline
authors.initials: C
authors.lastname: Legrand
authors.forename: Delphine
authors.initials: D
authors.lastname: Parron
authors.forename: Francoise
authors.initials: F
authors.lastname: Girard
authors.forename: Abdelhak
authors.initials: A
authors.lastname: Bessif
authors.forename: Sonia
authors.initials: S
authors.lastname: Poli
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Vaugeois
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Le Poul
authors.forename: Sylvain
authors.initials: S
authors.lastname: Celanire
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000494:pharmacology* / Q000627:therapeutic use; D001570:Benzodiazepinones / Q000494:pharmacology* / Q000627:therapeutic use; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C574444:4-(3-(2,6-dimethylpyridin-4-yl)phenyl)-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo(b)(1,4)diazepin-2-one; D000928:Antidepressive Agents; D001570:Benzodiazepinones; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D001569:Benzodiazepines