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S32212: a novel 5-HT2C receptor inverse agonist / alpha2 adrenoceptor antagonist and potential antidepressant. 1. A mechanistic characterization.

Millan MJ, Mannoury LA Cour C, Chanrion B, Dupuis DS, DI Cara B, Audinot V, Cussac D, Newman-Tancredi A, Kamal M, Boutin JA, Jockers R, Marin P, Bockaert J, Muller O, Dekeyne A, Lavielle G.
J Pharmacol Exp Ther. 340(3):750-64, 2012


Though most antidepressants suppress serotonin (5-HT) and/or noradrenaline reuptake, blockade of 5-HT2C receptors and alpha2-adrenoceptors likewise enhances monoaminergic transmission. These sites are targeted by the urea derivative, S32212 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide). S32212 was devoid of affinity for monoamine reuptake sites, yet displayed pronounced affinity (pKi 8.2) for constitutively-active h5-HT2C(INI) receptors, behaving as an inverse agonist in reducing basal Galpha(q)-activation, [3H]inositol-phosphate production and the spontaneous association of h5-HT2C(INI)-R-LUC receptors with β-arrestin2-YFP. Further, upon 18 hrs pre-treatment, S32212 enhanced the plasma membrane expression of h5-HT2C(INI) receptors as visualized by confocal microscopy and quantified by "ELISA". Its actions were prevented by the neutral antagonist, 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-HT2C agonist, CP809,101, upon ventrotegmental dopaminergic neurones. S32212 also blocked 5-HT-induced Galpha(q) and PhospholipaseC activation at h5-HT2A and, less potently, h5-HT2B receptors, and suppressed discriminative stimulus properties of the 5-HT2A agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane in rats. S32212 manifested marked affinity for halpha2A (pKi 7.2), halpha2B (8.2) and halpha2C-adrenoceptors (7.4), at which it abolished noradrenaline-induced recruitment of Galpha(i3), Galpha(o), adenylyl cyclase and Extracellular-Regulated-Kinase1/2. Moreover, S32212 dose-dependently abolished discriminative stimulus effects of the alpha2-AR agonist, S18616. Finally, S32212 displayed negligible affinity for alpha1A-adrenoceptors, histamine H1 and muscarinic M1 receptors. In conclusion, S32212 behaves as an inverse agonist at h5-HT2C receptors, and as an antagonist at halpha2-adrenoceptors (and h5-HT2A receptors). Its promising profile in preclinical models potentially relevant to treatment of depression is described in the accompanying paper.