ANANDAMIDE CONFORMERS TO PROBE THE CANNABINOID RECEPTOR

描述：（申请人摘要） 内源性大麻模拟物类似物的系统研究， 花生四烯酸，具有长期的，健康相关的潜力，以进一步了解 这种神经递质的生化作用机制和新的 它所代表的神经化学系统 配体相互作用位点的作图和 受体亚型的鉴定是另外的目的。 还有， 类似物可以产生分离的药理作用 从而产生更特异的药物和生化探针， 感兴趣的活动。 这对药物的研究具有潜在的应用价值 滥用，大脑功能，和免疫调节。 的具体目标 建议的工作是设计，合成，药理学测试， 构象限制的花生四烯酸类似物的分子模拟 探索化学和计算数据的构象空间部分 建议作为anandamide的活性构象。 据推测， 大麻素酰胺的活性构象是弯曲或“J”状结构， 与活性大麻素在两种形状上都有显著的重叠 以及在其受体可接近表面的静电势。 锁定 预期这种构象将增强活性， 分离这类化合物的生物效应。 化合物 设计用于测试理论的是环约束结构，基于 花生四烯酸酰胺的分子动力学初步研究及化学报道 其他花生四烯酸衍生物，检查假设部门 构象空间与小，中，大环类似物。 化合物探索了无环链中弯曲位置的影响 20-anandamide的碳链，手性构型差异 中心，以及受各种因素影响的构象自由度 环系统 进一步理论化，π之间的相互作用 配体的电子和受体中的阳离子位点起关键作用 在绑定。 这是在具有增强和降低的pi的类似物中测试的。 以一种将构象和静电分离的方式 碳-碳双键的影响。 的推定代谢产物 由于它们是潜在的活性形式， 这类配体。 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， 完善随后的设计、综合和测试周期。 测试将 包括公认的受体结合试验，小鼠离体血管的抑制， 在小鼠体内测试，以确定 活性化合物

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.