Project 2

总体上的药物滥用问题，特别是大麻的广泛使用，使人们对大麻植物的化学和药理产生了关注。自发现大麻素受体以来的十年里，在大麻素领域取得了很大的进展。已经证实，至少有两种类型的大麻素受体：存在于中枢神经系统(CMS)内外的CB1受体和已发现的CB2受体 主要是在外围国家。目前已经发现了两种主要的内源性配体，花烷胺(AEA)和2-花生四烯基甘油(2-Ara-Gi)。也被称为内源性大麻素，它们同时存在于中枢和外周组织中。一些化学上不同和不同结构类别的化合物被发现是大麻素受体的配体，这些化合物与化学/结构没有关系。拟议的合成研究的目标是产生化学探针，这将有助于理解所涉及的机制和内源性大麻素在CMS和外周的作用。我们的具体目标是(1)开发大麻类CB1受体的变构调节剂，(2)开发DAGL-a抑制剂，(3)开发与大麻内源性代谢有关的酶的选择性抑制剂，以及(4)为其他项目的研究人员提供AEA、2-Ara-Gi和感兴趣的配体，以进行进一步的生物学测试。这些类似物的合成将为体外和体内研究提供内源性大麻素探针，结果可能为其他大麻素受体亚型指明方向，揭示参与脑功能的机制，并导致在炎症、疼痛、免疫反应、脑损伤和其他CMS相关疾病的神经保护方面的治疗药物。建议的研究将有助于我们了解这类重要化合物的药理作用，并为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.