Copinga S, Tepper P G, Grol C J, Horn A S, Dubocovich M L
Department of Medicinal Chemistry, University Centre for Pharmacy, University of Groningen, The Netherlands.
J Med Chem. 1993 Oct 1;36(20):2891-8. doi: 10.1021/jm00072a008.
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.
制备了一系列未取代和甲氧基取代的2-氨基四氢萘（4a-q），并评估了它们竞争2-[125I]碘褪黑素与鸡视网膜膜结合的能力，以及抑制[3H]多巴胺从兔视网膜中钙依赖性释放的效力。先导化合物2-乙酰氨基-8-甲氧基四氢萘（4j）在褪黑素受体上表现出中等亲和力（Ki = 46 nM）和效力（IC50 = 1.4 nM）。褪黑素受体最佳激动活性所需的结构要求如下。首先，酰胺基团应具有小的直链烷基，这对亲和力至关重要；其次，2-氨基四氢萘环8位的甲氧基取代基对褪黑素受体的最佳激动活性至关重要。我们得出结论，这一系列未取代和甲氧基取代的2-氨基四氢萘构成了一类非吲哚类褪黑素样药物，可作为药理学工具进一步表征褪黑素受体并阐明褪黑素的作用模式。
