1-(2-ALKANAMIDOETHYL)-6-METHOXYINDOLE DERIVATIVES - A NEW CLASS OF POTENT INDOLE MELATONIN ANALOGS

A new series of indole melatonin analogues, bearing the amido ethyl si de chain attached at the N-1 position of the indole nucleus, were synt hesized and tested for their affinity for the melatonin receptor isola ted from quail optic tecta in a series of in vitro ligand-binding expe riments using 2-[I-125]iodomelatonin as the labeled ligand. The biolog ical activity was evaluated using two models: effects on the forskolin -stimulated cAMP accumulation in explants from quail optic tecta and e valuation of the GTP gamma S index derived from competition experiment s performed in the absence or presence of GTP gamma S. Compounds 2a an d 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 o f the C-2 substituent by introducing Br, phenyl, or COOCH3 (2b-d) resu lted in a significantly enhanced affinity (in the picomolar range) and improved agonist biological activity. Compounds lacking the methoxy g roup and bearing an N-alicyclic group (2h-j) behaved as partial agonis ts or antagonists.