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 anandamide（花生四烯基乙醇酰胺）是调节剂家族的主要成员，参与调节许多生物作用，包括镇痛和炎症反应的特定方面。有人提出，anandamide 的酸同系物可能作为内源性物质存在。这一假设在一项研究中得以实现，该研究表明，N-花生四烯酰甘氨酸 (NAGly) 确实是许多组织的内源性成分，并且其含量高于 anandamide。 NAGly 的一个有趣特性是其对 FAAH 的有效抑制作用，FAAH 是主要负责终止 anandamide 作用的酶。 FAAH是一种丝氨酸水解酶，其晶体 最近发表了其结构，从而为合理研究 NAGly 的结构特征（赋予其抑制特性）开辟了道路。据报道，在体外和体内模型中，NAGly 治疗都会导致 anandamide 浓度大幅增加。因此，我们假设这种抑制作用是 NAGly 抗炎作用以及可能的其他作用（例如，抗炎作用）的基础。镇痛。该项目的一个主要目标是合成一系列NAGly类似物作为探针；这些将基于使用 FAAH 晶体结构的计算机辅助对接分析。这些类似物将作为 FAAH 抑制剂进行体外测试，并比较它们对炎症介质的影响。这些研究中出现的结构-活性数据将支持或反驳这一假设。 Anandamide 似乎参与了整个动物界的广泛调节功能。一些例子是：行为的感觉运动和动机方面的控制、植入的调节、低血压和心动过缓效应、认知和药物依赖性、人类怀孕的控制、睡眠-觉醒周期、记忆形成、运动活动、疼痛感知和调节的免疫反应。因此，NAGly 等可调节体内 anandamide 水平的药物可能是许多这些健康相关过程的有效调节剂。