SITE SPECIFIC CALCIUM BLOCKERS: STRUCTURAL REQUIREMENTS

这项建议的长远目标是澄清 分子构象和OSAR之间的一个重要类别， 心血管药物称为钙进入阻滞剂或钙通道 对手。 将采用X射线衍射方法获得 这些药物的分子构象数据。 立即 注意力将集中在一系列1，4-二氢吡啶类似物上 与重要的抗心绞痛药物硝苯地平有关。 特别感兴趣 将涉及硝苯地平的不对称酯类似物， 显示出明显的组织选择性， 心血管组织的兴奋-收缩偶联。 具体 待研究的化合物包括尼群地平，其降低升高的 外周血管阻力;尼莫地平，影响脑血管阻力; 血管舒张，血压无显著降低;以及 尼索地平，一种有效的股血管舒张剂， 血栓素合成酶，并保护对花生四烯酸诱导的突发性 通过防止血小板诱导的肺血栓形成而死亡。 这些药物的X射线膀胱造影分子构象将是 检查与OSAR相关的药物抑制效力， 芳环空间最小宽度verloop参数函数 取代基和组织选择性作为空间位阻和 酯基的亲脂特性。 将试图 将这些概念与二氢吡啶环平面的程度联系起来。 两 尼莫地平和尼索地平的一系列六芳环衍生物将 在这项研究中检查。

The long term objective of this proposal is to clarify the relationship between the molecular conformation and OSAR's of an important class of cardiovascular drugs known as calcium entry blockers or calcium channel antagonists. X-ray diffraction methods will be employed to obtain molecular conformational data for a number of these drugs. Immediate attention will be focused on a series of 1,4-dihydropyridine analogs related to the important anti-anginal drug nifedipine. Particular interest will be directed to the unsymmetric ester analogs of nifedipine which display pronounced tissue selectivity with regard to the inhibition of excitation-contraction coupling of cardiovascular tissue. Specific compounds to be investigated include nitrenedipine, which lowers elevated peripheral vascular resistance; nimodipine, which effects cerebral vasodilation without a substantial decrease in blood pressure; and nisoldipine, a potent femoral vasolilator which additionally inhibits thromboxan synthetase and protects against arachidonate-induced suddent death by preventing platelet-induced pulmonary thrombosis. The X-ray cystallographic molecular conformations of these drugs will be examined in relation to OSAR's which specify drug inhibitory potency as a function of the steric minimum width verloop parameter of the aryl ring substituents and tissue selectivity as a function of the steric and lipophilic characteristics of the ester groups. Attempts will be made to relate these concepts to the degree of dihydropyridine ring plane. Two series of six aryl ring derivatives of nimodipine and nisoldipine will be examined in this study.