ANANDAMIDE CONFORMERS TO PROBE THE CANNABINOID RECEPTOR

大麻素构象探索大麻素受体

• 批准号: 2458453
• 负责人: HERBERT H SELTZMAN
• 金额: $ 9.41万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458453
• 关键词: analog; animal tissue; arachidonate; cannabinoid receptor; drug design /synthesis /production; epididymis; laboratory mouse; molecular dynamics; neurotransmitters; protein isoforms; protein structure function; receptor binding; reproductive system pharmacology

DESCRIPTION: (Applicant's Abstract) The systematic study of analogs of the endogenous cannabimimetic, anandamide, has the long term, health related potential to further knowledge of the biochemical mechanism of action of this neurotransmitter and the new neurochemical system it represents. Mapping of ligand interaction sites and the identification of receptor subtypes are additional objectives. Also, analogs could be generated with dissociated pharmacological effects resulting in more specific drugs and biochemical probes with psycho dynamic activities of interest. These have potential application to studies of drug abuse, brain function, and immuno-modulation. The specific aims of the proposed work is the design, synthesis, pharmacological testing, and molecular modeling of conformationally restricted anandamide analogs to probe a sector of conformational space that chemical and computational data suggest as the active conformation of anandamide. It is theorized that the active conformation of anandamides is a bent or "J" like structure which exhibits remarkable overlap with active cannabinoids as regards both shape and electrostatic potentials at its receptor accessible surface. Locking such conformations is expected to enhance activities and potentially dissociate biological effects in this class of compounds. Compounds designed to test the theory are ring constrained structures, based on preliminary molecular dynamics studies of anandamide and reported chemistry of other arachidonic acid derivatives, that examines the hypothesized sector of conformational space with small, medium and macrocyclic ring analogs. The compounds explore the effects of the position of the bend in the acyclic 20-carbon chain of anandamide, the configurational differences at chiral centers, and the degree of conformational freedom as influenced by various ring systems. It is further theorized that interaction between the pi electrons of the ligand and cationic sites in the receptor play a key role in binding. This is tested in analogs with both enhanced and reduced pi character in a way that separates the conformational and the electrostatic effects of the carbon-carbon double bonds. Putative metabolites of anandamide and the analogs are examined as they are potential active forms of this class of ligands. The research program is designed to test and evolve an SAR theory and discover active analogs by computationally guided synthesis, in vitro and in vivo testing, and computational analysis to refine subsequent cycles of design, synthesis and testing. Testing will involve accepted receptor binding assays, inhibition of mouse isolated vas deferens twitch response, and in vivo testing in the mouse to identify active compounds.

描述：（申请人摘要） 内源性大麻模拟物类似物的系统研究， anandamide，具有长期的、与健康相关的进一步知识的潜力 这种神经递质作用的生化机制和新的 它代表的神经化学系统。 配体相互作用位点的绘图和 受体亚型的鉴定是额外的目标。 还， 可以产生具有分离药理作用的类似物 产生具有心理动力学的更具体的药物和生化探针 感兴趣的活动。 这些在药物研究中具有潜在的应用 滥用、脑功能和免疫调节。 该计划的具体目标 拟议的工作是设计、合成、药理测试和 构象限制的 anandamide 类似物的分子建模 探测化学和计算数据的构象空间部分 建议作为 anandamide 的活性构象。 从理论上讲， anandamides 的活性构象是弯曲的或“J”状结构， 在形状方面与活性大麻素表现出显着的重叠 和其受体可触及表面的静电势。 锁定 这种构象预计会增强活性并有可能 分离此类化合物的生物效应。 化合物 设计用于测试该理论的是环约束结构，基于 anandamide 的初步分子动力学研究和报道的化学 其他花生四烯酸衍生物，检查假设的部门 具有小环、中环和大环类似物的构象空间。 这些化合物探索了无环中弯曲位置的影响 20碳链的anandamide，手性构型差异 中心，以及受各种影响的构象自由度 环系统。 进一步推测 pi 之间的相互作用 配体的电子和受体的阳离子位点起着关键作用 在绑定中。 这在具有增强和降低 pi 的模拟中进行了测试 以分离构象和静电的方式表征 碳-碳双键的影响。 假定的代谢物 对 anandamide 及其类似物进行检查，因为它们是潜在的活性形式 属于此类配体。 该研究计划旨在测试和 发展 SAR 理论并通过计算引导发现活跃的类似物 合成、体外和体内测试以及计算分析 完善后续的设计、合成和测试周期。 测试将 涉及公认的受体结合测定，抑制小鼠离体血管 输精管抽搐反应，并在小鼠体内进行测试以确定 活性化合物。