Endocannabinoid Analogs as Anti-inflammatory Agents

作为抗炎剂的内源性大麻素类似物

• 批准号: 6951593
• 负责人: SUMNER HOWARD BURSTEIN
• 金额: $ 12.15万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951593
• 关键词: analog; anandamide; antiinflammatory agents; cannabinoids; cell growth regulation; chemical synthesis; clinical research; computer data analysis; drug design /synthesis /production; drug screening /evaluation; enzyme activity; gene expression; glycine; human subject; hydrolase; interleukin 1; interleukin 8; prostaglandin endoperoxide synthase; serine; stereoisomer; tumor necrosis factor alpha

The endocannabinoid anandamide (arachidonyl ethanolamide) is the principal member of a family of regulators that are involved in modulating a number of biological actions including analgesia and specific aspects of the inflammatory response. It has been suggested that acid congeners of anandamide could exist as endogenous substances. This hypothesis was realized in a study that showed that such a substance, N-arachidonylglycine (NAGly), is indeed an endogenous constituent of many tissues and occurs at levels higher than anandamide. An interesting property of NAGly is its potent inhibitory effect on FAAH, the enzyme primarily responsible for the termination of anandamide action. FAAH is a serine hydrolase whose crystal structure was recently published, thus, opening the way for the rational study of the structural features of NAGly that confer its inhibitory properties. It has been reported that NAGly treatment in both in vitro and in vivo models, leads to a robust increase in anandamide concentrations. We therefore hypothesize that this inhibitory action is the basis for the anti-inflammatory action of NAGly and possibly other actions, e.g. analgesia. A major goal of this project is to synthesize a series of NAGly analogs as probes; these will be based on computer assisted docking analysis using the crystal structure of FAAH. The analogs will be tested in vitro as inhibitors of FAAH and compared with their effects on mediators of inflammation. The structure-activity data that will emerge from these studies will either support or refute the hypothesis. Anandamide appears to be involved in a wide range of regulatory functions through out the animal kingdom. Some examples are: the control of sensorimotor and motivational aspects of behavior, the regulation of implantation, hypotensive and bradycardic effects, cognition and drug dependence, the control of human pregnancy, sleep- wakefulness cycle, memory formation, locomotor activity, pain perception and modulation of the immune response. Thus, agents such as NAGly that can regulate in vivo anandamide levels could be effective modulators of many of these health related processes.

内源性大麻素配胺（Arachidonyl乙醇酰胺）是一个调节剂家族的主要成员，参与调节许多生物学作用，包括镇痛和炎症反应的特定方面。有人提出，anandamide的酸同源物可能是内源性物质的。这一假设在一项研究表明，这种物质N-弧菌甘氨酸（nagly）确实是许多组织的内源成分，并且发生在高于Anandamide的水平上。纳格利（Nagly）的一个有趣特性是其对法族（Faah）的有效抑制作用，法族（Faah）的酶是主要造成anandamide作用终止的酶。 FAAH是一种丝氨酸水解酶，其晶体 因此，最近发表了结构，为赋予其抑制性能的Nagly结构特征的合理研究开辟了道路。据报道，在体外和体内模型中的nagly治疗都会导致蜘蛛胺浓度的强劲升高。因此，我们假设这种抑制作用是nagly和可能其他行动的抗炎作用的基础，例如镇痛。该项目的主要目标是将一系列nagly类似物综合为探针。这些将基于使用FAAH的晶体结构的计算机辅助对接分析。这些类似物将在体外测试为FAAH的抑制剂，并将其对炎症介质的影响进行比较。从这些研究中出现的结构活性数据将支持或反驳该假设。 在整个动物界，Anandamide似乎参与了广泛的调节功能。一些例子是：控制行为的感觉和动机方面，植入，降压和心动过膜作用，认知和药物依赖性，人类妊娠的控制，睡眠唤醒周期，记忆形成，伤害运动，疼痛感，疼痛感和免疫反应的调节。因此，像Nagly之类的药物可以调节体内仙境化水平，可能是许多与健康相关的过程的有效调节剂。