Synthesis of N1-Phenethyl Substituted Indole Derivatives as New Melatoninergic Agonists and Antagonists

Abstract

The potency of new indolic N1-phenethyl substituted melatoninergic ligands with and without methyl groups in the α and β position of the alkanamidoethyl side chain was examined using the pigment aggregation response in a clonal line of Xenopus laevis melanophores. The non 5-OMe substituted compounds, 8a—e, are all weak antagonists while introduction of the 5-OMe group, 9a—e, increases both agonist and antagonist activity except for 9c (R=C₃H₇), which is only an agonist and 9e (R=c-C₄H₇), which is only an antagonist. Introduction of an α-methyl group into the 5-OMe derivatives, 14a—e, reduces the agonist potency while introduction of a β-methyl group has only a small effect on either the agonist or antagonist potency. Double β-methyl substitution of the 5-OMe derivatives, 20a—e, generally increases the agonist potential (20c, R=C₃H₇ is the most potent agonist of the compounds described) and decreases the antagonist potency, except for 20a (R=CH₃), which is the most potent antagonist of this series of compounds.