Endocannabinoid Analogs as Anti-inflammatory Agents

内源性大麻酸二乙醇胺(花生四烯基乙醇胺)是调节包括镇痛和炎症反应的特定方面在内的许多生物学行为的调节剂家族的主要成员。已有研究表明，花青胺的酸性同系物可能以内源物质的形式存在。这一假说是在一项研究中实现的，该研究表明，这种物质N-花生四烯基甘氨酸(NAGLY)确实是许多组织的内源性成分，并且发生在高于花生胺的水平。NAGLY的一个有趣的特性是它对FAAH有很强的抑制作用，FAAH是一种主要负责终止ANANDAME作用的酶。FAAH是一种丝氨酸水解酶，其晶体 Structure最近被发表，从而为合理研究nAGLY的结构特征而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处理都会导致ANANDIAME浓度的强劲增加。因此，我们假设这种抑制作用是nAGLY的抗炎作用以及可能的其他作用的基础，例如镇痛。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的晶体结构的计算机辅助对接分析。这些类似物将在体外作为FAAH的抑制剂进行测试，并比较它们对炎症介质的影响。这些研究将产生的结构-活性数据将支持或驳斥这一假设。 阿南达胺似乎参与了整个动物界广泛的调节功能。例如：感觉运动和行为动机方面的控制，植入的调节，降压和心动过缓的影响，认知和药物依赖，人类怀孕的控制，睡眠-觉醒周期，记忆形成，运动活动，痛觉和免疫反应的调节。因此，像nAGLY这样可以调节体内ANANDAME水平的药物可能是许多这些与健康相关的过程的有效调节剂。

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.