Unique structure-activity relationship for 4-isoxazolyl-1,4-dihydropyridines.
Unique structure-activity relationship for 4-isoxazolyl-1,4-dihydropyridines.
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DOI：
10.1021/jm020354w
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发表时间：
2003-01
影响因子：
7.3
通讯作者：
G. Zamponi;S. Stotz;R. Staples;Tina M Andro;J. Nelson;V. Hulubei;A. Blumenfeld;N. R. Natale
中科院分区：
文献类型：
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作者：
G. Zamponi;S. Stotz;R. Staples;Tina M Andro;J. Nelson;V. Hulubei;A. Blumenfeld;N. R. Natale
合成并表征了一系列4-异恶唑基-1，4-二氢吡啶类化合物，并用膜片钳技术研究了它们与钙通道的相互作用。由此产生的构效关系(SAR)不同于4-芳基二氢吡啶(DHPs)，并且亲和力在较高的持有电位下显著增加。因此，在3‘-芳基异恶唑类似物中，p-Br>；p-Cl>；>；p-F；和p-Cl>；m-Cl>；o-Cl>；>；o-MeO。对其中四个类似物进行了单晶X射线衍射分析，发现它们都是O-exo构象。然而，计算出的旋转势垒表明，在生理条件下，围绕杂环之间的连接处进行旋转是可行的。变温核磁共振研究证实了这一计算。通过Striessnig的计算序列同源程序，从数据中得出了一个工作假设，解释了ID的唯一SAR。
A series of 4-isoxazolyl-1,4-dihydropyridines (IDs) were prepared and characterized, and their interaction with the calcium channel was studied by patch clamp analysis. The structure-activity relationship (SAR) that emerges is distinct from the 4-aryldihydropyridines (DHPs), and affinity increases dramatically at higher holding potentials. Thus, among the 3'-arylisoxazolyl analogues p-Br > p-Cl >> p-F, and p-Cl > m-Cl > o-Cl >> o-MeO. Four of the analogues were examined by single-crystal X-ray diffractometry, and all were found to adopt an O-exo conformation in the solid state. The calculated barrier to rotation, however, suggests that rotation about the juncture between the heterocyclic rings is plausible under physiological conditions. A variable-temperature NMR study confirmed the computation. With Striessnig's computational sequence homologation procedure, a working hypothesis was derived from the data that explains the unique SAR for IDs.