Synthesis, pharmacological characterization and QSAR studies on 2-substituted indole melatonin receptor ligands

A number of 6-methoxy-1-(2-propionylaminoethyl)indoles carrying properly se lected substituents at the C-2 indole position, were prepared and tested as melatonin receptor ligands. Affinities and intrinsic activities for the hu man cloned mt(1) and MT2 receptors were examined and compared with those of some 2-substituted melatonin derivatives recently described by us. A quant itative structure-activity relationship (QSAR) study of the sixteen 2-subst ituted indole compounds. 5a-k, 1, 8-11, using partial least squares (PLS) a nd multiple regression analysis (MRA) revealed the existence of an optimal range of lipophilicity for the C-2 indole substituent. There are also indic ations that planar, electron-withdrawing substituents contribute to the aff inity by establishing additional interactions with the binding pocket. No m t(1)/MT2 subtype selectivity was observed, with the relevant exception of t he 2-phenethyl derivative 5e which exhibited the highest selectivity for th e h-MT, receptor among all the compounds tested (MT2/mt(1) ratio of ca. 50) . Conformational analysis and superposition of 5e to other reported selecti ve MT2 ligands revealed structural and conformational similarities that mig ht account for the MT2/mt(1) selectivity of 5e. (C) 2001 Elsevier Science L td. All rights reserved.