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

A series of unsubstituted and methoxy-substituted 2-amidotetralins (4a–q was prepared and evaluated for their ability to compete 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.