4-Aminoethylpiperazinyl aryl ketones with 5-HT1A/5-HT7 selectivity

Abstract

The well-known 5-HT1A/5-HT7 selectivity issue was tackled by a new series of 4-aminoethylpiperazinyl aryl ketones (1a-1l) specifically designed to distinguish the two hydrophobic sites centered at the anchoring salt bridge. The 4-aminoethylpiperazinyl aryl ketones showed a wide spectrum of activity and selectivity for the 5-HT receptors depending on the type of the hydrophobic groups attached at the aryl piperazinyl ketone scaffold. Docking study of the most active compounds against 5-HT7R and 5-HT1AR revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge. These two binding sites are perpendicular to each other in 5-HT7R but parallel in 5-HT1AR, and this observation is well matched with the previous report which claimed that 5-HT7R affinity arises from bent conformation of the bound ligand whereas an extended one is best suited for 5-HT1AR selectivity. Also, as these pockets have different size and shape, inhibitory activity as well as selectivity of the 4-aminoethylpiperazinyl aryl ketones against 5-HT7R and 5-HT1AR seemed to be determined by combination of two hydrophobic substituents attached at both ends of the title compounds. (C) 2011 Elsevier Ltd. All rights reserved.