Synthesis and biological evaluation of (phenylpiperazinyl-propyl)arylsulfonamides as selective 5-HT(2A) receptor antagonists.

Abstract A novel series of 5-HT 2A ligands that contain a (phenylpiperazinyl-propyl)arylsulfonamides skeleton was synthesized. Thirty-seven N -(cycloalkylmethyl)-4-methoxy- N -(3-(4-arylpiperazin-1-yl)propyl)-arylsulfonamide and N -(4-(4-arylpiperazin-1-yl)butan-2-yl)-arylsulfonamide compounds were obtained. The binding of these compounds to the 5-HT 2A , 5-HT 2C , and 5-HT 7 receptors was evaluated. Most of the compounds showed IC 50 values of less than 100 nM and exhibited high selectivity for the 5-HT 2A receptor. Among the synthesized compounds, 16a and 16d showed good affinity at 5-HT 2A (IC 50  = 0.7 nM and 0.5 nM) and good selectivity over 5-HT 2C (50–100 times) and 5-HT 7 (1500–3000 times).