N-acetyl-5-arylalkoxytryptamine analogs: Probing the melatonin receptors for MT 1-selectivity

Abstract

A series of melatonin analogs obtained by the replacement of the ether methyl group with larger arylalkyl and aryloxyalkyl substituents was prepared in order to probe the melatonin receptors for MT 1-selectivity. The most MT 1-selective agents 11 and 15 were substituted with a Ph(CH 2) 3 or a PhO(CH 2) 3 group. Compounds 11 and 15 displayed 11.5-fold and 11-fold higher affinity for the MT 1 receptors than for the MT 2 subtype. Interestingly, in our binding assay 11 and 15 have shown considerably higher MT 1-affinity and selectivity than the reference ligand, the dimeric agomelatine 1a. The synthesis and pharmacological evaluation of a novel series of MLT analogs obtained by replacing the ether methyl group with arylalkyl and aryloxyalkyl moieties is described here. The results indicate for compounds 11 and 15 considerably higher MT 1-affinity and selectivity than the reference ligand, the dimeric agomelatine 1a. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.