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

The potency of new indolic N1-phenethyl substituted melatoninergic ligands with and without methyl groups in the a and b 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 (R5C3H7), which is only an agonist and 9e (R5c-C4H7), which is only an antagonist. Introduction of an a-methyl group into the 5-OMe derivatives, 14a—e, reduces the agonist potency while introduction of a bmethyl group has only a small effect on either the agonist or antagonist potency. Double b-methyl substitution of the 5-OMe derivatives, 20a—e, generally increases the agonist potential (20c, R5C3H7 is the most potent agonist of the compounds described) and decreases the antagonist potency, except for 20a (R5CH3), which is the most potent antagonist of this series of compounds.