RS-102221: A novel high affinity and selective, 5-HT(2C) receptor antagonist

Abstract

The 5-HT(2C) receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT(2A) and 5-HT(2B) selective antagonists have been described. However, no 5-HT(2C) selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT(2C) receptors, we have developed a selective 5-HT(2C) receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,6-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pK(i) = 8.4) and rat (pK(i) = 8.5) 5-HT(2C) receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT(2C) receptor as compared to the 5-HT(2A) and 5-HT(2B) 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-HT(2C) 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-HT(2C) receptor antagonist to be described.