SITE SPECIFIC CALCIUM BLOCKERS: STRUCTURAL REQUIREMENTS

这项建议的长远目标是澄清 分子构象和一组重要的 心血管药物称为钙通道剂。 特别感兴趣 将重点关注硝苯地平家族的1，4-二氢吡啶类药物， 集中在两个方面：确定那些特征， 区分激动剂和拮抗剂，并阐明这些激动剂和拮抗剂的作用。 特别是负责选择效力的特征 心血管组织 X射线衍射方法将用于获得 一些重要化合物的分子构象数据， 包括内酯激动剂CGP 28的各种芳基取代的类似物 392，以及与尼群地平相关的组织选择性拮抗剂， 尼莫地平。 将努力解决外消旋制剂的 各种组织选择性类似物以提供 将进行重复测试，以确定手性 选择性活动的偏好。 X射线衍射方法，采用 反常散射，将被用来确定绝对配置 这些组织选择性类似物显示出明显的对映体 的特异性 MM 2 P分子力学程序将用于 证实了晶体学观察到的分子构象， 解决不遵守反式-反式二酯是否是 更高的构象能量或这种构象不能 与环境形成氢键。 晶体构象 数据将为确定适当的半经验值提供基础 对于这些计算中使用的参数，特别是那些涉及 氮的化学功能 这些拟议的研究将增加已成为 近年来关于配体-受体的手性 相互作用和受体通道门控状态的循环。 从最初的研究阶段获得的晶体学数据强烈 表明存在有限数量合理配体-受体 结合模型描述了这些药物如何稳定 Ca 2+通道的主动开放或非主动关闭状态。 拟议 研究将提供答案，这将进一步澄清这一性质， 药物-受体相互作用的立体化学特征 需要这些分子激活或激活Ca 2+通道，或 增强特定组织选择性反应。 这些信息将有助于 设计更有效的药物。

The long term objective of this proposal is to clarify the relationship between the molecular conformation and activities of an important group of cardiovascular drugs known as Ca2+ channel agents. Particular interest will be focused on the nifedipine family of 1,4-dihydropyridine drugs and concentrate on two areas: the determination of those features which distinguish agonists from antagonists, and the elucidation of those features which are responsible for selective potency in particular cardiovascular tissues. X-ray diffraction methods will be used to obtain molecular conformational data for a number of important compounds which are to include various aryl-substituted analogs of the lactone agonist, CGP 28 392, and tissue selective antagonists related to nitrendipine and nimodipine. Efforts will be extended to resolve racemic preparations of the various tissue selective analogs to provide enantiomeric samples which will be pharmacologically tested to determine the extent of chiral preference for selective activity. X-ray diffraction methods, employing anomalous scattering, will be used to determine the absolute configurations of those tissue selective analogs which show pronounced enantiomeric specificity. The MM2P molecular mechanics programs will be used to corroborate the crystallogaphically observed molecular conformations and resolve whether the non-observance of trans-trans di-esters is the result of a higher conformational energy or the inability of such conformers to hydrogen bond to their environment. The crystallographic conformational data will provide the basis to determine appropriate semi-empirical values for the parameters used in these calculations, especially those involving nitrogenous chemical functions. These proposed studies will augment the information which has become available in recent years regarding the chirality of the ligand-receptor interaction and the cycling of receptor-channel gating states. Crystallographic data obtained from the initial study period strongly suggest that there are a limited number of plausible ligand-receptor binding models which describe how these drugs may stabilize either the active open or inactive closed states of the Ca2+ channel. The proposed studies will provide answers which will further clarify the nature of this drug-receptor interaction by delineating the stereochemical characteristics required of these molecules to activate or inactivate the Ca2+ channel or enhance particular tissue selective response. This information will aid the design of more effective drugs.