SITE SPECIFIC CALCIUM BLOCKERS: STRUCTURAL REQUIREMENTS

这项建议的长期目标是澄清这一关系 一类重要化合物的分子构象与OSAR之间的关系 称为钙通道阻滞剂或钙通道的心血管药物 对抗者。将使用X射线衍射法来获得 其中一些药物的分子构象数据。立马 将重点关注一系列1，4-二氢吡啶类似物 与重要的抗心绞痛药物硝苯地平有关。特殊利益 将针对硝苯地平的不对称酯类似物，它 显示出明显的组织选择性，关于抑制 心血管组织的兴奋-收缩偶联。特定的 要研究的化合物包括尼群地平，它能降低升高的 外周血管阻力；影响大脑的尼莫地平 血管扩张而血压不会大幅下降；以及 尼索地平是一种有效的股动脉扩张剂，它还能抑制 血栓素合成酶及其对花生四烯酸诱导的心肌损伤的保护作用 通过预防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的关系，OSAR指定药物抑制效力为 芳环的空间最小宽度Verloop参数的函数 取代基和组织选择性作为空间和空间的函数 酯基的亲油性特征。我们将尝试 将这些概念与二氢吡啶环平面的程度联系起来。二 尼莫地平和尼索地平的六个芳环衍生物系列将被 在这项研究中进行了检查。

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.