ANANDAMIDE CONFORMERS TO PROBE THE CANNABINOID RECEPTOR

描述：(申请人摘要) 内源性大麻类似物的系统研究， 阿南达胺，具有长期、健康相关的潜力，有待进一步了解 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。配基相互作用部位和配基相互作用部位图 受体亚型的鉴定是额外的目标。另外， 类似物可以产生分离的药理作用 导致更多特定的药物和具有心理动力学的生化探针 感兴趣的活动。这些在药物研究中具有潜在的应用价值。 虐待、大脑功能和免疫调节。《公约》的具体目标 建议的工作是设计、合成、药理测试和 构象受限的氨基甲酰胺类似物的分子模拟 探索化学和计算数据的一段构象空间 提示为花青胺的活性构象。从理论上讲， 烷胺类化合物的活性构象是一种弯曲的或“J”形结构，它 在两种形状上都显示出与活性大麻素的显著重叠 以及其受体可接近表面的静电势。锁定 这种构象有望增强活动，并有可能 在这类化合物中分离生物学效应。化合物 设计用于测试该理论的是环形约束结构，基于 双胺类化合物的分子动力学初步研究及报道化学 其他花生四烯酸衍生品，它检查了假设的部门 具有小、中、大环环类似物的构象空间。 这些化合物探索了非环中弯曲位置的影响。 苯乙酰胺的20-碳链，在手性上的构型差异 中心，以及各种因素对构象自由度的影响 环状系统。进一步推论，圆周率之间的相互作用 受体中配基和阳离子位置的电子起着关键作用。 在装订中。这在增强和简化pi的模拟中进行了测试 以一种分离构象和静电的方式表现的 碳-碳双键的影响。推定的代谢物 由于双胺及其类似物是潜在的活性形式，因此对它们进行了研究 属于这类配体的。这项研究计划旨在测试和 发展合成孔径雷达理论并通过计算指导发现活跃的类似物 合成，体外和体内测试，和计算分析 完善后续的设计、综合和测试周期。测试将会 涉及公认的受体结合试验，抑制小鼠分离的血管 输精管的抽搐反应，并在小鼠体内试验进行鉴定 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.