2-Amido-8-methoxytetralins: A series of nonindolic melatonin-like agents

Abstract

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 (Ki = 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.

Analogues of diverse structure are unable to differentiate native melatonin receptors in the chicken retina, sheep pars tuberalis and Xenopus melanophores

“…Conceivably, analogues based on a tetralin or naphthalene nucleus -not tested in the present study -may be able to discriminate Mel, receptor subtypes (Yous et al, 1992;Copinga et al, 1993). Alternatively, the Mel, receptor subtypes may exhibit very similar or identical pharmacological specificity, differing perhaps, in their distribution, regulation or coupling to intracellular second messenger systems.…”

Structural requirements at the melatonin receptor

“…First, a resurgence of interest in the pharmacology of melatonin has led to the synthesis and testing of novel analogues of melatonin by several groups. In particular, several novel series of potent melatonin analogues based on either a tetraline nucleus (Copinga et al, 1993) or a naphthalene nucleus (Yous et al, 1992) have recently been described. In addition, we have synthesized a series of highaffinity, conformationally restricted tetrahydrocarbazole analogues of melatonin (Garratt et al, 1994) in which the amide side-chain has limited flexibility.…”

Regio‐ and Stereoselective Biohydroxylations with a Recombinant Escherichia coli Expressing P450pyr Monooxygenase of Sphingomonas Sp. HXN‐200

“…For instance, they can be used to prepare pharmacologically active 2-aminotetralins which show affinity to the melatonin receptor. [17] Several synthetic routes have been developed via the reduction of 2-tetralone [18a-c] or cycloalkylation of arylalkyl epoxide.…”