%0 Journal Article %A John Dunlop %A Stephanie W. Watts %A James E. Barrett %A Joseph Coupet %A Boyd Harrison %A Hossein Mazandarani %A Stanley Nawoschik %A Menelas N. Pangalos %A Siva Ramamoorthy %A Lee Schechter %A Deborah Smith %A Gary Stack %A Jean Zhang %A Guoming Zhang %A Sharon Rosenzweig-Lipson %T Characterization of Vabicaserin (SCA-136), a Selective 5-Hydroxytryptamine 2C Receptor Agonist %D 2011 %R 10.1124/jpet.111.179572 %J Journal of Pharmacology and Experimental Therapeutics %P 673-680 %V 337 %N 3 %X The 5-hydroxytryptamine 2C (5-HT2C) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT2C 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 a comprehensive strategy to assess 5-HT2B receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced 125I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT2C receptor sites in Chinese hamster ovary cell membranes with a Ki value of 3 nM and was >50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT2B receptor subtype using [3H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC50, 8 nM; Emax, 100%) in stimulating 5-HT2C receptor-coupled calcium mobilization and exhibited 5-HT2A receptor antagonism and 5-HT2B antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT2B receptors, vabicaserin failed to induce a 5-HT2B receptor-dependent contraction and produced a rightward shift of the 5-HT and α-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT2B competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT2B receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT2B receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT2B receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT2C receptor agonist. %U https://jpet.aspetjournals.org/content/jpet/337/3/673.full.pdf