New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities
New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities
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DOI：
10.1021/jm9803267
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发表时间：
1998-12-31
影响因子：
7.3
通讯作者：
Gasco, A
中科院分区：
文献类型：
--
作者：
Di Stilo, A;Visentin, S;Gasco, A
合成了一系列4-苯基-1,4-二氢吡啶，在苯基环的邻位和间位上取代给no呋喃嘧啶基团及其不释放no的呋喃嘧啶类似物，并对其进行了药理学表征。这些化合物的血管扩张活性在大鼠主动脉上进行了评估，并在鸟苷酸环化酶亚甲基蓝（MB）和1H-[1,2,4]恶二唑[4,3-a]喹诺沙林-1-(ODQ)抑制剂存在时以EC50值或EC50iGC值表示。通过[H-3]-尼群地平在大鼠皮质匀浆上的位移实验，确定了Ca2+通道上对1,4- dhp受体的亲和力，以IC50值表示。不能释放NO的化合物的IC50值与EC50值呈线性相关。含有no供体部分的衍生物的EC50calcd值，其血管扩张活性的Ca2+阻断成分的表达，被插值到这个线性回归中。它们与存在可溶性鸟苷酸环化酶抑制剂时测定的EC50iGC值具有良好的对应关系。分析(EC50EC50)-E-iGC/比值提供了一个有用的工具来区分平衡良好的杂合体和偏向于Ca2+阻断或no依赖性血管扩张剂活性的衍生物。由于4-苯基环邻位和间位的取代，对1,4- dhp受体的亲和力产生了不利影响。提出用SAR来解释这种效应。
A series of 4-phenyl-1,4-dihydropyridines substituted at the ortho and meta positions of the phenyl ring with NO-donating furoxan moieties and their non-NO-releasing furazan analogues were synthesized and pharmacologically characterized. The vasodilator activities of these compounds were evaluated on rat aorta and expressed as EC50 values or as EC50iGC values when obtained in the presence of inhibitors of guanylate cyclase methylene blue (MB) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-(ODQ). Affinities to 1,4-DHP receptors on Ca2+ channels, expressed as IC50 values, were determined through displacement experiments of [H-3]-nitrendipine on rat cortex homogenates. A linear correlation between IC50 and EC50 values was found for compounds unable to release NO. EC50calcd values for derivatives containing NO-donor moieties, expression of the Ca2+-blocking component of their vasodilator activity, were interpolated on this linear regression. They showed a good correspondence with EC50iGC values determined in the presence of soluble guanylate cyclase inhibitors. Analysis of (EC50EC50)-E-iGC/ ratios provided a useful tool to distinguish well-balanced hybrids from derivatives biased toward Ca2+-blocking or NO-dependent vasodilator activity. A detrimental effect on affinity to the 1,4-DHP receptor, due to substitution at the ortho and meta positions of the 4-phenyl ring, was observed. SAR to explain this effect is proposed.