ANANDAMIDE--STRUCTURE ACTIVITY RELATIONSHIPS

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， 大麻素的化学和药理学， 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，鉴定了与该受体结合的内源性配体 如花生四烯乙醇酰胺，命名为花生四烯酰胺（AN）。 之甚少 已知这种配体，但它属于一类化合物， 类花生酸 无明显化学/结构活性 在anandamide系列的关系（SAR）。 我们认为这将是 对于理解AN和大麻素如何与相同的物质相互作用至关重要。 识别位点。 我们的具体目标是：（1）系统地开发AN系列SAR， 改变乙醇胺部分，例如通过改变链长， 氮和OH基团，将OH变为非氢键合基团， 氮、硫等; (2)通过改变花生四烯酸来开发SAR 部分，例如通过改变链中双键的数量，包括 总饱和度，改变链长，支化和取代 链末端由-OCH（CH 3）CH 2CH 2CH 2 Ph和-OCH（CH 3）C5 H11形成。 这些副 已知链赋予有效的大麻素活性;（3）研究 各种烷基取代对氮和α-羟基的影响 AN中羰基的位置。 这些取代基将在空间上影响 AN中酰胺键的代谢分解。 此外，我们还有 提出了类似物的合成，其中酰胺键被取代， AN中的甲醛基团。 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SAR，并将突出显示 该系列和THC之间可能存在的差异，并允许更好的 了解它们的相互关系。 这些数据可以让我们 大麻素受体亚型的方向，甚至有助于发现 一个拮抗剂。 此外，他们还将提供大麻素探针， 体外和体内研究。 因此，拟议的研究将有助于 我们对这一重要类别的药理作用的理解 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.