title: S32212, a novel serotonin type 2C receptor inverse agonist/α2-adrenoceptor antagonist and potential antidepressant: I. A mechanistic characterization.
abstract: Although most antidepressants suppress serotonin (5-HT) and/or noradrenaline reuptake, blockade of 5-HT(2C) receptors and α(2)-adrenoceptors likewise enhances monoaminergic transmission. These sites are targeted by the urea derivative N- [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide (S32212). S32212 was devoid of affinity for monoamine reuptake sites, yet displayed pronounced affinity (pK(i), 8.2) for constitutively active human 5-HT(2CINI) (h5-HT(2CINI)) receptors, behaving as an inverse agonist in reducing basal Gα(q) activation, [(3)H]inositol-phosphate production, and the spontaneous association of h5-HT(2CINI)-Renilla luciferase receptors with β-arrestin2-yellow fluorescent protein. Furthermore, upon 18-h pretreatment, S32212 enhanced the plasma membrane expression of h5-HT(2CINI) receptors as visualized by confocal microscopy and quantified by enzyme-linked immunosorbent assay. Its actions were prevented by the neutral antagonist 6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl]indoline-1-carboxamide (SB242,084), which also impeded the induction by long-term exposure to S32212 of otherwise absent Ca(2+) mobilization in mouse cortical neurones. In vivo, S32212 blunted the inhibitory influence of the 5-HT(2C) agonist 2-(3-chlorobenzyloxy)-6-(1-piperazinyl)pyrazine (CP809,101) on ventrotegmental dopaminergic neurones. S32212 also blocked 5-HT-induced Gα(q) and phospholipase C activation at the h5-HT(2A) and, less potently, h5-HT(2B) receptors and suppressed the discriminative stimulus properties of the 5-HT(2A) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane in rats. S32212 manifested marked affinity for human α(2A)- (pK(i) 7.2), α(2B)- (pK(i) 8.2), and α(2C)- (pK(i) 7.4) adrenoceptors, at which it abolished noradrenaline-induced recruitment of Gα(i3), Gα(o), adenylyl cyclase, and extracellular-regulated kinase1/2. Moreover, S32212 dose-dependently abolished the discriminative stimulus effects of the α(2)-adrenoceptor agonist (S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(1',2',3',4'-tetrahydronaphthalene)] (S18616). Finally, S32212 displayed negligible affinity for α(1A)-adrenoceptors, histamine H(1) receptors, and muscarinic M(1) receptors. In conclusion, S32212 behaves as an inverse agonist at h5-HT(2C) receptors and as an antagonist at human α(2)-adrenoceptors (and h5-HT(2A) receptors). Its promising profile in preclinical models potentially relevant to the treatment of depression is described in J Pharmacol Exp Ther 340:765-780, 2012.
authors.affiliation: Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy/Seine, France. mark.millan@fr.netgrs.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Clotilde
authors.initials: C
authors.lastname: Mannoury la Cour
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chanrion
authors.forename: Delphine S
authors.initials: DS
authors.lastname: Dupuis
authors.forename: Benjamin
authors.initials: B
authors.lastname: Di Cara
authors.forename: Valérie
authors.initials: V
authors.lastname: Audinot
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
authors.forename: Maud
authors.initials: M
authors.lastname: Kamal
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Olivier
authors.initials: O
authors.lastname: Muller
authors.forename: Anne
authors.initials: A
authors.lastname: Dekeyne
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lavielle
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D054314:Drug Inverse Agonism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010410:Penile Erection / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000928:Antidepressive Agents; D007211:Indoles; C571288:N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-1,2-dihydro-3-H-benzo(e)indole-3-carboxamide; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium