Characterization of Vabicaserin (SCA-136), a Selective 5-Hydroxytryptamine 2C Receptor Agonist

• DOI: 10.1124/jpet.111.179572
• Publication Date: 2011-03-15T19:08:39Z
• Authors: John Dunlop; Stephanie W. Watts; James E. Barrett; Joseph Coupet; Boyd Harrison; Hossein Mazandarani; Stanley Nawoschik; Menelas N. Pangalos; Siva Ramamoorthy; Lee Schechter; Deborah Smith; Gary Stack; Jean Zhang; Guoming Zhang; Sharon Rosenzweig...
• Keywords: Competitive antagonist

The 5-hydroxytryptamine 2C (5-HT_2C) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in wide variety of disorders. Here, we describe the vitro pharmacological profile novel 5-HT_2C receptor-selective agonist vabicaserin [(−)-4,5,6,7,9,9a,10,11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including comprehensive strategy to assess 5-HT_2B selectivity using diverse preparations and assays activation. Vabicaserin displaced ¹²⁵I-(2,5-dimethoxy)phenylisopropylamine binding from human sites Chinese hamster ovary cell membranes with <i>K</i>_i value 3 nM was &gt;50-fold selective over number serotonergic, noradrenergic, dopaminergic receptors. Binding affinity determined [³H]5HT 14 nM. potent full (EC₅₀, 8 nM; <i>E</i>_max, 100%) stimulating receptor-coupled calcium mobilization exhibited 5-HT_2A antagonism antagonist or partial activity transfected cells, depending on level expression. In rat stomach fundus colonic longitudinal muscle endogenously expressing receptors, failed induce receptor-dependent contraction produced rightward shift 5-HT α-methyl-5-HT concentration-response curves these preparations, respectively, consistent competitive antagonism. Likewise, receptor-mediated arteries deoxycorticosterone acetate-salt-treated rats, model hypersensitized function, 5-HT-induced response that summary, is novel, potent, agonist.