NON PSYCHOACTIVE CANNABINOIDS WITH THERAPEUTIC POTENTIAL

具有治疗潜力的非精神活性大麻素

• 批准号: 6378830
• 负责人: SUMNER HOWARD BURSTEIN
• 金额: $ 24.58万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-11 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378830
• 关键词: RNase protection assay; analgesics; antiinflammatory agents; binding sites; cannabinoid receptor; cannabinoids; chemical structure function; drug screening /evaluation; human tissue; laboratory mouse; laboratory rat; pharmacokinetics; pharmacology; receptor binding; tissue /cell culture

The broad goal of this application is to establish that the THC acids represent a distinct class of cannabinoids which have been reported not to bind to either of the known cannabinoid receptors. Although showing no psychotropic activity, they display certain of the pharmacological activities associated with the use of marijuana. The acids occur naturally as metabolites of THC and, as such, can be detected readily in the tissues of marijuana users. The properties of the acids, shown in experimental models, suggest that they may be of interest as candidates for medicinal agents. These include actions as analgesics and antiinflammatory drugs with a low potential for abuse and a minimum of toxic side effects. In this proposal, two approaches will be used to answer the question of whether or not the acid metabolites of THC have a role in the actions of the parent compound. First, attempts will be made to discover high affinity, saturable binding sties for the cannabinoid acids using high specific activity, radiolabelled acid derivatives. Structure-activity binding protocols to be included will be aimed at showing stereospecificity and rank orders that resemble the potencies of the acids in the various systems. Second, possible mechanisms for the antiinflammatory effects of the acids will be investigated and compared with the primary cannabinoids to look for differences as well as similarities. Experiments will be done to determine their effects on cytokines, eicosanoids and metalloproteinases in human cell culture systems. Where feasible, in vivo correlates will be examined to show relevance for all of the above studies. The findings that will be generated from this proposal might provide a possible solution to the current controversy over the medical use of marijuana. This would be accomplished by the discovery of synthetic analogs of THC, the active principal of marijuana, that would provide the medicinal benefits of Cannabis without the accompanying mood altering effects and abuse potential.

本申请的主要目标是确定 THC 酸代表一类独特的大麻素，据报道它们不会与任何一种已知的大麻素受体结合。 尽管没有表现出精神活性，但它们表现出某些与使用大麻相关的药理活性。 这些酸作为 THC 的代谢物天然存在，因此可以在大麻使用者的组织中轻松检测到。 实验模型中显示的酸的特性表明它们可能作为药物候选者感兴趣。 其中包括作为镇痛药和抗炎药的作用，滥用可能性低且毒副作用最小。在该提案中，将使用两种方法来回答 THC 的酸性代谢物是否在母体化合物的作用中起作用的问题。 首先，将尝试使用高比活性、放射性标记的酸衍生物来发现大麻素酸的高亲和力、可饱和结合位点。 所包含的结构-活性结合方案旨在显示立体特异性和类似于各种系统中酸的效力的排序。 其次，将研究酸的抗炎作用的可能机制，并将其与主要大麻素进行比较，以寻找差异和相似之处。 将进行实验以确定它们对人类细胞培养系统中的细胞因子、类二十烷酸和金属蛋白酶的影响。 在可行的情况下，将检查体内相关性以显示与所有上述研究的相关性。该提案的研究结果可能为当前有关大麻医疗用途的争议提供可能的解决方案。 这将通过发现大麻的活性成分四氢大麻酚（THC）的合成类似物来实现，该类似物将提供大麻的药用价值，而不会伴随情绪改变作用和滥用潜力。