title: Characterization of vabicaserin (SCA-136), a selective 5-hydroxytryptamine 2C receptor agonist.
abstract: The 5-hydroxytryptamine 2C (5-HT(2C)) 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-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 a comprehensive strategy to assess 5-HT(2B) receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced (125)I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT(2C) receptor sites in Chinese hamster ovary cell membranes with a K(i) 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-HT(2B) receptor subtype using [(3)H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC(50), 8 nM; E(max), 100%) in stimulating 5-HT(2C) receptor-coupled calcium mobilization and exhibited 5-HT(2A) receptor antagonism and 5-HT(2B) 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-HT(2B) receptors, vabicaserin failed to induce a 5-HT(2B) 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-HT(2B) competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT(2B) receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT(2B) receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT(2B) receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT(2C) receptor agonist.
authors.affiliation: Neuroscience Research Unit, Pfizer Global Research and Development, Eastern Point Road, MS8220-4220, Groton, CT 06340, USA. john.dunlop@pfizer.com
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Watts
authors.forename: James E
authors.initials: JE
authors.lastname: Barrett
authors.forename: Joseph
authors.initials: J
authors.lastname: Coupet
authors.forename: Boyd
authors.initials: B
authors.lastname: Harrison
authors.forename: Hossein
authors.initials: H
authors.lastname: Mazandarani
authors.forename: Stanley
authors.initials: S
authors.lastname: Nawoschik
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Siva
authors.initials: S
authors.lastname: Ramamoorthy
authors.forename: Lee
authors.initials: L
authors.lastname: Schechter
authors.forename: Deborah
authors.initials: D
authors.lastname: Smith
authors.forename: Gary
authors.initials: G
authors.lastname: Stack
authors.forename: Jean
authors.initials: J
authors.lastname: Zhang
authors.forename: Guoming
authors.initials: G
authors.lastname: Zhang
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006576:Heterocyclic Compounds, 4 or More Rings / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000378:metabolism* / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011994:Recombinant Proteins; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; C042390:alpha-methylserotonin; D012701:Serotonin; C556517:vabicaserin