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; 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：（申请人的摘要） 内源性大麻的类似物的系统研究， anandamide具有长期，与健康有关的潜力，以进一步知识 该神经递质和新的动作的生化机制 它代表的神经化学系统。 配体相互作用位点的映射和 受体亚型的识别是其他目标。 还， 可以通过解离的药理学作用产生类似物 通过心理动态产生更具体的药物和生化探针 感兴趣的活动。 这些潜在地用于药物研究 滥用，大脑功能和免疫调节。 特定目标 拟议的工作是设计，合成，药理测试和 构象限制的anandamide类似物的分子模型 探测化学和计算数据的构象空间的扇区 暗示是Anandamide的主动构象。 理论上是 Anandamides的主动构象是弯曲的或“ J”的结构 在形状方面表现出与活性大麻素的显着重叠 以及其受体可进入表面的静电电势。 锁定 这种构象有望增强活动，并可能 在这类化合物中解离生物学作用。 化合物 旨在测试理论的是基于环的约束结构 初步的分子动力学研究，并报道了化学 研究假设的扇形 具有小，中和大环类似物的构象空间。 这些化合物探索弯曲位置在无环中的效果 20碳链anandamide，手性的构型差异 中心以及受各种影响的构象自由程度 环系统。 进一步的理论是PI之间的相互作用 配体的电子和受体中的阳离子位点起着关键作用 在结合中。 这是在增强和降低的类似物中测试的 特性以分离构象和静电的方式 碳碳双键的影响。 推定的代谢物 肛门胺和类似物是潜在的活动形式的检查 这类配体。 该研究计划旨在测试和 通过计算指导来发展SAR理论并发现主动类似物 合成，体外和体内测试以及计算分析 完善随后的设计，合成和测试周期。 测试将 涉及公认的受体结合测定，抑制小鼠分离的VA deferens Twitch响应和鼠标中的体内测试以识别 活性化合物。