Endocannabinoid Analogs as Anti-inflammatory Agents

内源性大麻素anandamide（花生四烯酸乙醇酰胺）是调节剂家族的主要成员，其参与调节许多生物作用，包括镇痛和炎症反应的特定方面。有人认为，大麻素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，这种物质N-花生四烯酰甘氨酸（NAGly）确实是许多组织的内源性成分，其水平高于花生四烯酰胺。NAGly的一个有趣的特性是其对FAAH的有效抑制作用，FAAH是主要负责终止花生四烯酸酰胺作用的酶。FAAH是丝氨酸水解酶，其晶体 结构最近发表，因此，为合理研究赋予其抑制特性的NAGly的结构特征开辟了道路。据报道，在体外和体内模型中NAGly处理导致大麻素浓度的稳健增加。因此，我们假设这种抑制作用是NAGly的抗炎作用和可能的其他作用（例如镇痛）的基础。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的晶体结构的计算机辅助对接分析。类似物将在体外作为FAAH抑制剂进行测试，并与它们对炎症介质的作用进行比较。从这些研究中获得的结构-活性数据将支持或反驳这一假设。 花生四烯酸似乎参与了广泛的调节功能，通过了动物王国。以下是一些示例：感觉运动和行为动机方面的控制、植入的调节、兴奋和心动过缓效应、认知和药物依赖、人类妊娠的控制、睡眠-觉醒周期、记忆形成、运动活动、疼痛感知和免疫反应的调节。因此，可以调节体内大麻素水平的试剂如NAGly可以是许多这些健康相关过程的有效调节剂。

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.