ANANDAMIDE--STRUCTURE/ACTIVITY RELATIONSHIPS

描述(申请人摘要)： 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 植物大麻的唾液。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(CB1)，以及 花生四烯基乙醇胺(AN)被鉴定为花生四烯基乙醇酰胺(AN) 内源性配体。这项计划的长期目标是发展 二十烷酸类ANS的结构-活性关系(SAR)，以及 与大麻素没有化学/结构关系。我们感觉到特区 对于了解AN和大麻素的相互作用至关重要 具有相同的受体。目前的重点将放在 开发(1)有效的激动剂和潜在的拮抗剂；(2)新的 结构类似物；(3)作为潜在代谢物的羟基-AN类似物；(4) 选择性酰胺酶抑制剂。所有这些目标都代表着 目前的节目已经产生了几个值得注意的线索。 具体目的是：(1)继续检测花生四烯酸的相对分子质量 部分硝酸铵；(2)继续考察硝酸乙醇胺部分的SAR； (3)合成羟基化AN类似物：(4)开发新的AN/THC类似物； (5)开发一种选择性强的酰胺酶抑制剂。 这些类似物的合成及其随后的生物学评价 将为我们提供AN系列中的SAR，并将突出区别 它可能存在于此系列和THC之间，并允许更好的 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，他们还将为这两家公司提供大麻类探头 体外和体内研究。因此，拟议的研究将有助于我们的 对这一重要类中药药理作用的认识 化合物。

DESCRIPTION (Applicant's Abstract): 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 saliva. 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 (CB1), and arachidonylethanolamide called anandamide (AN), was identified as the endogenous ligand. The long term goal of this program is to develop the Structure-Activity Relationships (SAR) of ANs which are eicosanoids, and bear no chemical/structural relationship with cannabinoids. We feel the SAR of ANs will be critical for understanding how AN and cannabinoids interact with the same receptor. The present emphasis will be directed toward developing (1) potent agonists and potential antagonists; (2) novel structural analogs; (3) hydroxy-AN analogs as potential metabolites and (4) selective amidase inhibitors. All these goals represent a continuation of the current program which has generated several noteworthy leads. The specific aims are to (1) continue to examine the SAR of arachidonic acid part of AN; (2) continue to examine the SAR of the ethanolamine part of AN; (3) synthesize hydroxylated AN analogs; (4) develop novel AN/THC analogs; (5) develop a selective and potent amidase inhibitor. The synthesis of these analogs and their subsequent biological evaluation will provide us 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.