1‐(2‐Alkanamidoethyl)‐6‐methoxyindole Derivatives: A New Class of Potent Indole Melatonin Analogues.

A new series of indole melatonin analogues, bearing the amido ethyl side chain attached at the N-1 position of the indole nucleus, were synthesized and tested for their affinity for the melatonin receptor isolated from quail optic tecta in a series of in vitro ligand-binding experiments using 2-[125I]iodomelatonin as the labeled ligand. The biological activity was evaluated using two models:  effects on the forskolin-stimulated cAMP accumulation in explants from quail optic tecta and evaluation of the GTPγS index derived from competition experiments performed in the absence or presence of GTPγS. Compounds 2a and 2k−n, obtained by shifting the methoxy group and the ethylamido side chain from the C-5 and C-3 positions of melatonin to the C-6 and N-1 positions of the indole nucleus, exhibited an affinity similar to that of melatonin itself, as well as full agonist activity. Optimization of the C-2 substituent by introducing Br, phenyl, or COOCH3 (2b−d) resulted in a significantly enhanced affinity (in the pi...