SYNTHESIS OF ISOTOPE-LABELED CB LIGANDS FOR NMR STUDIES

用于 NMR 研究的同位素标记 CB 配体的合成

• 批准号: 6400226
• 负责人: Xiang-Qun Xie
• 金额: $ 2.4万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6400226
• 关键词: analog; cannabinoid receptor; cannabinoids; chemical binding; chemical models; chemical structure function; chemical synthesis; computer simulation; drug design /synthesis /production; ligands; mathematical model; model design /development; molecular dynamics; molecular site; nuclear magnetic resonance spectroscopy

DESCRIPTION (Applicant's Abstract): Since the two cannabinoid receptor subtypes (CB1, CB2) have been identified as a subgroup of the Gi protein-coupled seven-transmembrane-spanning receptor superfamily, a great effort has been directed toward understanding the molecular-level interactions between the CB receptor and its ligand, as well as designing novel cannabimimetic ligands possessing therapeutically useful biological properties but devoid of the psychotropic effects of marijuana. However, many unanswered questions about the molecular-level interactions between the receptor and the cannabimimetic ligands, the nature of the receptor active site(s), and their three-dimensional structures remain to be addressed. The objective of this research proposal is to obtain information on the molecular properties of cannabimimetic agents in membranes (in order to mimic the receptor environment) through the combined use of nuclear magnetic resonance (NMR) and computer modeling methods. Such information is of critical importance for the design of novel analogs of potential therapeutic value. The conformational properties of a judiciously chosen group of analogs related to three known cannabimimetic groups, namely arachidonylethanolamides (AEAs), aminoalkylindoles (AAIs), and pyrazoles (PRZs) will be studied using NMR methods and then refined using computer modeling approaches. 1) A special effort will be made to study the conformations of these molecules in a membrane environment. The 3D structure of the ligand in the membrane will be obtained using a variety of NMR techniques including multidimensional NMR experiments with pulse gradients, Transfer NOE and Rotational Echo Double Resonance experiments. 2) Computer modeling will be used to refine the NMR-determined conformations. Comparative Molecular Field Analysis (CoMFA) and the Active Analog Approach will be applied to examine the definition of pharmacophores and to define the active site as well as to map receptor volume. The pharmacophoric model defined by NMR experiments and theoretical calculations can be used as a guide for designing novel CB ligands and predicting the biological behavior of other untested compounds. The procedures developed will eventually be used to directly study the conformation of receptor-bound ligands in the future. Overall, the studies will provide insights into the design of a new generation of ligands possessing enhanced biological activity.

描述(申请人摘要)： 由于大麻素受体的两个亚型(CB1、CB2)已被鉴定 作为GI蛋白偶联七跨膜蛋白的一个亚群 受体超家族，人们已经付出了巨大的努力来理解 CB受体与其配体AS之间的分子水平相互作用 以及设计具有治疗作用的新型拟大麻配体 有用的生物学特性，但缺乏精神药物的作用 大麻。然而，关于分子水平的许多悬而未决的问题 受体与拟大麻配体的相互作用，自然界 受体活性部位(S)及其三维结构 仍有待解决。这项研究提案的目的是 获取关于大麻仿真剂的分子特性的信息 膜(为了模拟受体环境)通过结合 使用核磁共振和计算机模拟方法。是这样的 信息对于设计新的类似物至关重要 潜在的治疗价值。明智的分子的构象性质 与三个已知的大麻仿制基团有关的选定类似物组，即 花生四烯基乙醇酰胺(AEA)、氨基烷基吲哚(AAI)和吡唑类化合物 (PRZ)将使用核磁共振方法进行研究，然后使用计算机进行精炼 建模方法。1)将特别努力研究 这些分子在膜环境中的构象。3D 膜中配体的结构将使用各种方法获得 包括PULSE多维核磁共振实验在内的核磁共振技术 梯度、转移NOE和旋转回波双共振实验。 2)将使用计算机模拟来精炼由核磁共振确定的 构象。比较分子场分析(CoMFA)及其活性 将采用类比方法来审查药效团的定义 并确定活性部位以及绘制受体体积图。这个 由核磁共振实验和理论计算确定的药效模型 可作为设计新型CB配体和预测Cb配体的指导。 其他未经测试的化合物的生物学行为。制定的程序 最终将用于直接研究受体结合的构象 未来的配基。总体而言，这些研究将提供对 新一代生物增强型配体的设计 活动。