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

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