SYNTHESIS OF SR141716A AND ANANDAMIDE 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。虽然在这方面取得了迅速的进展， 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，拮抗剂SR 141716 A，一种吡唑衍生物， 发现了这些与化学/结构没有明显的关系。 大麻素拟议的合成研究的目标是产生 化学探针，这将有助于了解这些不同的 结构如THC（δ 9-THC）、类二十烷酸（AN）、氨基烷基吲哚 (AAI)拮抗剂SR 141716 A与相同的识别 绝佳的价钱我们的具体目标是合成（1）具有很高活性的 可以作为药理学/生物化学探针的效力。（二） SR 141716 A类似物，将鉴别SR 141716 A中的亲脂性位点， 从而为分子建模提供关键信息， 研究大麻素药效团（3）内源性配体和 拮抗剂SR 141716 A大量（几克），并使它们 可用于进一步的生物学研究。 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 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 rapid 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, an antagonist SR141716A, a pyrazole derivative has 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 (delta9-THC), eicosanoids (AN), aminoalkylindoles (AAI) and the antagonist SR141716A interact with the same recognition site. Our Specific Aims are to synthesize (1) A analogs of very high potency which could act as pharmacological/biochemical probes. (2) SR141716A analogs which will identify the lipophilic site in SR141716A and thus provide critical information in molecular modeling for alignment studies with the cannabinoid pharmacophore (3) endogenous ligands and the antagonist SR141716A in large quantities (several grams) and make them available 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 cannabinoid receptor subtypes. The proposed study will therefore help our understanding of the pharmacological action of this important class of compounds.