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: D W Bonhaus, K K Weinhardt, M Taylor, A DeSouza, P M McNeeley, K Szczepanski, D J Fontana, J Trinh, C L Rocha, M W Dawson, L A Flippin, R M Eglen
• Journal: Neuropharmacology (Neuropharmacology) 1997 Apr-May Vol. 36 Issue 4-5 Pg. 621-9 ISSN: 0028-3908 [Print] England
• PMID: 9225287 (Publication Type: Journal Article)

Chemical References

• 8-(5-(5-amino-2,4-dimethoxyphenyl)-5-oxopentyl)-1,3,8-triazaspiro(4.5)decane-2,4-dione
• Ligands
• Receptors, Serotonin
• Serotonin Antagonists
• Spiro Compounds
• Sulfonamides
• Hydrogen

Topics

• Animals
• CHO Cells
• Cell Membrane (drug effects, metabolism)
• Cricetinae
• Feeding Behavior (drug effects)
• Female
• Guinea Pigs
• Humans
• Hydrogen (metabolism)
• Ligands
• Male
• Motor Activity (drug effects)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin (drug effects, metabolism)
• Serotonin Antagonists (pharmacology)
• Spiro Compounds (pharmacology)
• Sulfonamides (pharmacology)
• Weight Gain (drug effects)