5-HT2C receptor selectivity and structure-activity relationship of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs

Abstract

Agonists of the 5-HT2C receptor have attracted much attention as therapeutic agents for the treatment of obesity. Subtype selectivity against other 5-HT2 receptors is one of the most important prerequisites for reducing side effects. We present the synthesis of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs and their structure–activity relationship studies on 5-HT2A and 5-HT2C receptors. Although the compounds showed nanomolar activity to the 5-HT2C receptor, their selectivity against the 5-HT2A receptor was modest to low. Molecular modeling studies using homology modeling and docking simulation revealed that selectivity originated from subtype specific residues. The observed binding modes and receptor–ligand interactions provided us a clue for optimizing the selectivity against the 5-HT2A receptor.