5-HT 2C receptor selectivity and structure-activity relationship of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs

摘要

Agonists of the 5-HT 2C receptor have attracted much attention as therapeutic agents for the treatment of obesity. Subtype selectivity against other 5-HT 2 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-HT 2A and 5-HT 2C receptors. Although the compounds showed nanomolar activity to the 5-HT 2C receptor, their selectivity against the 5-HT 2A 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-HT 2A receptor.