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

一般的药物滥用问题和大麻的广泛使用， 特别是集中注意力在化学和药理学的 种植大麻。虽然在空袭方面取得了进展， 化学和药理学的研究， 产生各种中枢神经效应的机制 尚未建立。几年前，研究表明大麻素 通过与大脑中的G蛋白偶联受体结合而起作用， 最近，一个名为anandamides（AN）的内源性配体家族， 一种叫做类二十烷酸的化合物。在 此外，CB 1拮抗剂SR 141716 A和CB 2拮抗剂SR 144528，两者均 已经发现了吡唑衍生物。这些没有明显的 与大麻素的化学/结构关系。的目标 拟议的合成研究是产生化学探针，这将有助于 在理解THC（Δ/9-THC）等不同结构， 类花生酸（AN）、氨基烷基吲哚（AAI）和拮抗剂SR 141716 A 与相同的识别位点相互作用。我们的具体目标是（1） 继续合成SR 141716 A类似物（2）优化拮抗剂 O-1248的活性;（3）合成O-1248的类似物 （4）合成第二代AN类似物（5）合成AN/THC 混合物（6）重新合成特定的杂环和碳环THC（7） 继续向该集团供应AN和感兴趣的配体， 生物学研究。 这些类似物的合成及其随后的生物学评价 将突出不同类型之间可能存在的差异 一种类似大麻的药物此外，他们还将提供大麻素探针， 无论是在体外还是在体内的研究和数据可以指向我们在 其他大麻素受体亚型的方向。拟定的研究将 因此有助于我们了解这种药物的药理作用， 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.