2-Amido-8-methoxytetralins: A Series of Nonindolic Melatonin-like Agents

Article abstract of DOI:10.1021/jm00072a008

A series of unsubstituted and methoxy-substituted 2-amidotetralins (4a-q) was prepared and evaluated for their ability to complete for 2-<125I>iodomelatonin binding to chicken retinal membranes and for their potency to inhibit the calcium-dependent release of <3H>dopamine from rabbit retina.The lead compound, 2-acetamido-8-methoxytetralin (4j), showed a moderate affinity (K_i = 46 nM) and potency (IC50 = 1.4 nM) at the melatonin receptor.The structural requirements necessary for optimal agonistic activity at the melatonin receptor are as follows.First, the amido group, which should have a small, nonbranched alkyl group, is essential for affinity, and second, the methoxy substituent at the 8-position of the 2-amidotetralin ring is essential for optimal agonistic activity at the melatonin receptor.We concluded that this series of unsubstituted and methoxy-substituted 2-amidotetralins constitutes a class of nonindolic melatonin-like agents that can be used as pharmacological tools to further characterize melatonin receptors and to elucidate the mode of action of melatonin.