SITE SPECIFIC CALCIUM BLOCKERS: STRUCTURAL REQUIREMENTS

这项建议的长期目标是澄清这一关系 在分子构象和活性之间的一个重要基团 被称为钙通道药物的心血管药物。特殊利益 将重点放在硝苯地平家族的1，4-二氢吡啶类药物和 集中在两个方面：确定哪些特征 激动剂与拮抗剂的区别及其解释 特别是对选择性效力负责的特征 心血管组织。将使用X射线衍射法获得 一系列重要化合物的分子构象数据 包括内酯激动剂CGP 28的各种芳基取代类似物 392，以及与尼群地平和尼群地平相关的组织选择性拮抗剂 尼莫地平。将继续努力解决外消旋制剂的问题 各种组织选择性类似物以提供对映体样品 将进行药理测试以确定手性的程度 对选择性活动的偏好。X射线衍射法，采用 反常散射，将用于确定绝对构型 在那些显示出明显的对映体的组织选择性类似物中 专一性。MM2P分子力学程序将用于 证实了晶体学观察到的分子构象和 解决不遵守反式双酯是否是 具有较高的构象能或这样的构象分子不能 氢键与它们的环境相连。晶体构象 数据将为确定适当的半经验值提供基础 这些计算中使用的参数，特别是那些涉及 含氮化学功能。 这些拟议的研究将增加已经成为 近年来关于配体-受体手性的研究进展 受体-通道门控状态的相互作用和循环。 从最初的研究阶段获得的结晶学数据 提示可能存在数量有限的配体-受体 结合模型描述了这些药物如何稳定 钙离子通道的主动开放或非主动关闭状态。建议数 研究将提供答案，进一步澄清这一问题的性质 用立体化学性质描述药物-受体相互作用 激活或失活钙通道所需的这些分子或 增强特定组织的选择性反应。这一信息将有助于 设计出更有效的药物。

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.