文章基本信息

标题：Structure–Activity Relationships of Receptor Binding of 1,4-Dihydropyridine Derivatives
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作者：Daiki Takahashi ; Luvsandorj Oyunzul ; Satomi Onoue 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2008
卷号：31
期号：3
页码：473-479
DOI：10.1248/bpb.31.473
出版社：The Pharmaceutical Society of Japan
摘要：The present study was undertaken to investigate binding activity of synthesized 1,4-dihydropyridine (1,4-DHP) derivatives (Compounds 1—124) to 1,4-DHP calcium channel antagonist receptors in rat brain. Sixteen 1,4-DHP derivatives inhibited specific (+)-[³H]PN 200–110 binding in rat brain in a concentration-dependent manner with IC₅₀ value of 0.43 to 3.49 μ M . Scatchard analysis revealed that compounds 54, 69, 85, like nifedipine, caused a significant increase in apparent dissociation constant ( K _d) for (+)-[³H]PN 200–110, while compounds 68, 69 and 80 caused a significant decrease in maximal number of bindings sites ( B _max). These data suggest that compounds 68, 69 and 80 exert longer-acting antagonistic effects of 1,4-DHP receptors than compounds 54, 69 and 85. The structure–activity relationship study has revealed that 1) ester groups in 3- and 5-positions are the most effective, 2) the aryl group in the 4-position of 1,4-DHP ring is the basic requirement for optimal activity, 3) position and type of electron-withdrawing groups on phenyl group at position 4 would affect the receptor-binding activity. Furthermore, compound 58 exerted α1 receptor binding activity, being 1.6 times greater than 1,4-DHP receptors. Compounds 81, 84, 91, 94, 106, 108 and 109 showed significant binding of ATP-sensitive potassium (K_ATP) channel, and the binding activities of compounds 81, 84, 108 and 109 were 1.6—3.8 times greater than the binding activity for 1,4-DHP receptors. Compounds 91 and 106 had similar binding activity for K_ATP channel and 1,4-DHP receptors. In conclusion, the present study has shown that novel 1,4-DHP derivatives exert relatively high binding affinity to 1,4-DHP receptors and has revealed new aspect of structure–activity relationships of 1,4-DHP derivatives, especially hexahydroquinoline derivatives.
关键词：1,4-dihydropyridine;hexahydroquinoline derivative;structure–activity relationship;L-type calcium channel antagonist receptor