ANANDAMIDE--STRUCTURE ACTIVITY RELATIONSHIPS

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。尽管在这方面取得了快速的进展 这种叫做大麻素的化合物的化学和药理作用， 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 最近，与该受体结合的内源性配体被鉴定出来。 作为花生四烯基乙醇胺，被命名为双乙酰胺(AN)。不是很多 已知这种配体，但它属于一类化合物，称为 二十烷类化合物。这些化合物没有明显的化学/结构活性。 阿南达胺系列中的关系(SAR)。我们觉得这将是 对于理解AN和大麻素如何与 识别站点。 我们的具体目标是：(1)有系统地发展特区 改变乙醇胺部分，例如通过改变链长 氮和羟基，将羟基改变为非氢键基团， 氮、硫等；(2)通过改变花生四烯酸来开发合成孔径雷达 部分，例如通过改变链中的双键数目，包括 总饱和度，改变链长，分支和替换 末端的链由-Och(CH3)CH2CH2Ph和-Och(CH3)C5H11组成。这一边 已知链具有强大的大麻素活性；(3)研究 不同烷基取代对氮和α-烷基取代的影响 氨基中的羰基的位置。这些取代基会立体地影响 氨键的新陈代谢分解。此外，我们还有 建议合成类似物，其中的酰胺键被一个 An中的羟甲基。 这些类似物的合成及其随后的生物学评价 将在AN系列中提供IS与SAR，并将突出 此系列与THC之间可能存在的差异，并允许更好地 了解他们之间的相互关系。这些数据可能会告诉我们 大麻素受体亚型的方向甚至有助于发现 一个敌手的。此外，他们还将为 包括体外和体内研究。因此，拟议的研究将有所帮助。 在我们对这一重要类别的药理作用的理解中 一种化合物。

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 ad 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, the endogenous ligand which binds to this receptor was identified as arachidonylethanolamide, given the name anandamide (AN). Not much is known about this ligand but it belongs to a class of compounds called eicosanoids. These have no obvious chemical/structure-Activity Relationships (SAR) in the anandamide series. We feel this will be critical for understanding how AN and cannabinoids interact with the same recognition site. Our specific aims are (1) to develop SAR in AN series by systematically changing the ethanolamine part e.g. by changing the chain length between nitrogen and OH groups, changing the OH to nonhydrogen bonding groups, nitrogen, sulfur etc.; (2) to develop SAR by changing the arachidonic acid part e.g. by changing the number of double bonds in the chain including total saturation, changing the chain length, branching and substituting the chain at the end by -OCH(CH3)CH2CH2CH2Ph and -OCH(CH3)C5H11. These side chains are known to impart potent cannabinoid activity; (3) to study the effect of substitution by various alkyl groups on nitrogen and in the alpha position of the carbonyl in AN. These substituents will sterically affect the metabolic breakdown of the amide bond in AN. In addition we have proposed the synthesis of analogs in which the amide bond is replaced by an oxymethylene group in AN. The synthesis of these analogs and their subsequent biological evaluation will provide is with SAR in the AN series and will highlight the differences which may exist between this series and THCs and allow a better understanding of their interrelationship. The data could point us in the direction of cannabinoid receptor sub-types and even help in the discovery of an antagonist. In addition they will provide cannabinoid probes for both in vitro and in vivo studies. The proposed study will therefore help in our understanding of the pharmacological action of this important class of compounds.