SYNTHESIS OF SR141716A AND ANANDAMIDE ANALOGS

SR141716A 和花生四烯酸类似物的合成

• 批准号: 6238028
• 负责人: RAJ RAZDAN
• 金额: $ 15.87万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6238028
• 关键词: analog; cannabinoid receptor; cannabinoids; chemical synthesis; eicosanoids; neuropharmacology; pyrazoles

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.

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 近年来，一个内源性配体家族被命名为anandamide(AN)，属于 到一类被称为二十烷类化合物的化合物，已经被鉴定。在……里面 此外，拮抗剂SR141716A，一种吡唑衍生物已经被 被发现了。这些化合物没有明显的化学/结构关系。 大麻素。拟议的合成研究的目标是产生 化学探针将有助于理解这种多样性是如何 结构如四氢呋喃(Delta9-THC)、二十烷基类化合物(AN)、氨基烷基吲哚 (AAI)和拮抗剂SR141716A相互作用 地点。我们的具体目标是合成(1)非常高的类似物 药效，可作为药理/生化探针。(2) SR141716A类似物，用于鉴定SR141716A和SR141716A中的亲脂位点 从而在用于比对的分子建模中提供关键信息 大麻素类药效团的研究(3)内源性配体和 大量(几克)拮抗剂SR141716A，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 将重点介绍各种类型之间可能存在的差异 卡那比仿生学。此外，他们还将为 体外和体内的研究和数据可能会告诉我们 大麻素受体亚型的方向。拟议的研究将 因此有助于我们对其药理作用的了解 一类重要的化合物。