SYNTHESIS OF ANANDAMIDE, 2-ARA-GL AND SR 14176A ANALOGS

毒品滥用问题和#年大麻的广泛使用 特别是集中在化学和药理学上的 大麻属植物。尽管在突袭方面取得了进展 这种叫做大麻素的化合物的化学和药理学， 产生各种中枢神经效应的机制 还没有建立起来。几年前，有研究表明，大麻类物质 通过与大脑中的G蛋白偶联受体结合来发挥作用 近年来，一个内源性配体家族被命名为anandamide(AN)，属于 到一类被称为二十烷类化合物的化合物，已经被鉴定。在……里面 此外，CB1拮抗剂SR141716A和CB2拮抗剂SR144528，均为 人们已经发现了吡唑的衍生物。这些都没有明显的 与大麻素的化学/结构关系。的目标是 拟议的合成研究将产生化学探针，这将有助于 为了理解像THC(Delta/9-THC)这样的多样化结构是如何， 二十烷酸(AN)、氨基烷基吲哚(AAI)和拮抗剂SR141716A 与相同的识别站点交互。我们的具体目标是(1) 继续合成SR141716A类似物(2)优化拮抗剂 我们实验室发现的O-1248的活性(3)合成类似物 2-Ara-Gl(4)合成第二代AN类似物(5)合成AN/THC 杂化化合物(6)重新合成特定的杂环和碳环THC(7) 继续向集团供应感兴趣的AN和配体，以便进一步 生物学研究。 这些类似物的合成及其随后的生物学评价 将重点介绍各种类型之间可能存在的差异 卡那比仿生学。此外，他们还将为 体外和体内的研究和数据可能会告诉我们 其他大麻素受体亚型的方向。拟议的研究将 因此有助于我们对其药理作用的了解 一类重要的化合物。

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. Although raid advances have been made in the chemistry and pharmacology of this class of compound called cannabinoids, the mechanisms involved in producing the various central nervous effects have not been established. A few years ago, it was shown that cannabinoids act by binding to a G-protein-coupled receptor in the brain and very recently, a family of endogenous ligands named anandamides (AN) belonging to a class of compounds called eicosanoids, has been identified. In addition, a CB1 antagonist SR141716A and a CB2 antagonist SR144528, both pyrazole derivatives have been discovered. These have no obvious chemical/structural relationship with cannabinoids. The goal of the proposed synthetic research is to generate chemical probes which will help in understanding how such diverse structures as THC's (delta/9-THC), eicosanoids (AN), aminoalkylindoles (AAI) and the antagonist SR141716A interact with the same recognition site. Our Specific Aims are to (1) continue the synthesis of SR141716A analogs (2) optimize the antagonist activity of O-1248 discovered in our laboratory (3) synthesize analogs of 2-Ara-Gl (4) synthesize second generation AN analogs (5) synthesize AN/THC hybrids (6) resynthesize specific heterocyclic and carbocyclic THCs (7) continue the supply of AN and ligands of interest to the group for further biological studies. The synthesis of these analogs and their subsequent biological evaluation will highlight the differences which may exist between the various types of canabimimetics. In addition they will provide cannabinoid probes for both in vitro and in vivo studies and the data could point us in the direction of other cannabinoid receptor-subtypes. The proposed study will therefore help our understanding of the pharmacological action of this important class of compounds.