Project 2

毒品滥用问题，特别是大麻的广泛使用，尤其集中在 关注大麻属植物的化学和药理作用。在自那以来的十年里 自从大麻素受体被发现以来，在大麻素领域取得了很大的进展。它有 已经确定至少有两种类型的大麻素受体：CB1受体，它们是 存在于中枢神经系统(CMS)内外，以及已发现的CB2受体 主要是在外围国家。目前已发现两种主要的内源性配体，即脱氢表雄胺(AEA)和 2-花生四烯基甘油(2-Ara-Gi)。也称为内源性大麻素，它们都存在于中央作为 以及周围组织。几种化学上截然不同且结构多样的化合物 它们没有化学/结构关系，已被发现是大麻素的配体 感受器。拟议的合成研究的目标是产生化学探针，这将有助于 了解内源性大麻素在细胞质雄性不育和 外围设备。我们的具体目标是：(1)开发大麻类化合物CB1的变构调节剂 受体，(2)DAGL-a抑制剂的开发，(3)选择性酶抑制剂的开发 参与内源性大麻素代谢和(4)供应AEA、2-Ara-Gi和感兴趣的配体 其他项目的调查人员正在进行进一步的生物测试。类似物的合成将提供 用于体外和体内研究的内源性大麻素探针，结果可以为我们指明方向 其他大麻素受体亚型，揭示了参与大脑功能的机制并导致 治疗药物在颅脑损伤的炎症、疼痛、免疫反应和神经保护方面的作用 以及其他与CMS相关的疾病。建议的研究将有助于我们理解药理作用 这类重要化合物的作用，并在医疗保健领域提供药物。

The drug abuse problem in general and the widespread use of marijuana in particular have focused attention on the chemistry and pharmacology of the plant Cannabis sativa. In the decade since the discovery of the cannabinoid receptors, much progress has been made in the cannabinoid field. It has been established that there are at least two types of cannabinoid receptors: CB1 receptors which are present both inside and outside the central nervous system (CMS) and CB2 receptors which are found mainly in the periphery. Two main endogenous ligands have been discovered, anandamide (AEA) and 2-arachidonyl-glycerol (2-Ara-GI). Also known as endocannabinoids, they are both present in central as well as peripheral tissues. Several chemically distinct and diverse structural classes of compounds which have no chemical/ structural relationships have been discovered as ligands for the cannabinoid receptors. The goal of the proposed synthetic research is to generate chemical probes which will help in understanding the mechanisms involved and the role of endocannabinoids in the CMS and the periphery. Our Specific Aims are (1) development of allosteric modulators of the cannabinoids CB1 receptors, (2) development of DAGL-a inhibitors, (3) development of selective inhibitors of enzymes involved in endocannabinoid metabolism and (4) supply AEA, 2-Ara-GI and ligands of interest to investigators for the other projects for further biological testing. The synthesis of the analogs will provide endocannabinoid probes for the in vitro and in vivo studies and the results could point us in the direction of other cannabinoid receptor subtypes, reveal mechanisms involved in brain function and lead to therapeutic drugs in the areas of inflammation, pain, immune response, neuroprotection in head injury and other CMS related diseases. The proposed study will help our understanding of the pharmacological action of this important class of compounds and provide drugs in the health care field.