title: RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist.
abstract: The 5-HT2C receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT2A and 5-HT2B selective antagonists have been described. However, no 5-HT2C selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT2C receptors, we have developed a selective 5-HT2C receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pKi = 8.4) and rat (pKi = 8.5) 5-HT2C receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT2C receptor as compared to the 5-HT2A and 5-HT2B receptors. RS-102221 acted as an antagonist in a cell-based microphysiometry functional assay (pA2 = 8.1) and had no detectable intrinsic efficacy. Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats. Surprisingly, RS-102221 failed to reverse the hypolocomotion induced by the 5-HT2 receptor agonist 1-(3-chlorophenyl)piperazine (m-CPP). It is concluded that RS-102221 is the first selective, high affinity 5-HT2C receptor antagonist to be described.
authors.affiliation: Institute of Pharmacology, Roche Bioscience, Palo Alto, CA 94304, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Bonhaus
authors.forename: K K
authors.initials: KK
authors.lastname: Weinhardt
authors.forename: M
authors.initials: M
authors.lastname: Taylor
authors.forename: A
authors.initials: A
authors.lastname: DeSouza
authors.forename: P M
authors.initials: PM
authors.lastname: McNeeley
authors.forename: K
authors.initials: K
authors.lastname: Szczepanski
authors.forename: D J
authors.initials: DJ
authors.lastname: Fontana
authors.forename: J
authors.initials: J
authors.lastname: Trinh
authors.forename: C L
authors.initials: CL
authors.lastname: Rocha
authors.forename: M W
authors.initials: MW
authors.lastname: Dawson
authors.forename: L A
authors.initials: LA
authors.lastname: Flippin
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006859:Hydrogen / Q000378:metabolism; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C107821:8-(5-(5-amino-2,4-dimethoxyphenyl)-5-oxopentyl)-1,3,8-triazaspiro(4.5)decane-2,4-dione; D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D013449:Sulfonamides; D006859:Hydrogen