ANANDAMIDE--STRUCTURE/ACTIVITY RELATIONSHIPS

阿南达酰胺--结构/活性关系

• 批准号: 6497786
• 负责人: RAJ RAZDAN
• 金额: $ 13.43万
• 依托单位: ORGANIX, INC.
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497786
• 关键词: amidases; analog; anandamide; arachidonate; cannabinoids; chemical structure function; chemical synthesis; enzyme inhibitors; ethanolamines

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.

描述（申请人摘要）： 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 种植大麻唾液 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（CB 1）结合而起作用， 花生四烯酸乙醇酰胺，又称花生四烯酸乙醇酰胺（AN）， 内源性配体 该计划的长期目标是开发 类花生酸AN的构效关系（SAR），以及 与大麻素没有化学/结构关系。 我们觉得特区 对于了解AN和大麻素如何相互作用至关重要 相同的受体。 目前的重点将针对 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，以及（4） 选择性酰胺酶抑制剂。 所有这些目标都是 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）继续研究花生四烯酸的SAR （2）继续考察AN乙醇胺部分的SAR; (3)合成羟基化AN类似物;（4）开发新型AN/THC类似物; (5)开发一种选择性和有效的酰胺酶抑制剂。 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，并将突出显示 这可能存在于这个系列和THC之间，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 了解这类重要的药物的药理作用， 化合物.