NON PSYCHOACTIVE CANNABINOIDS WITH THERAPEUTIC POTENTIAL

具有治疗潜力的非精神活性大麻素

• 批准号: 6175550
• 负责人: SUMNER HOWARD BURSTEIN
• 金额: $ 23.86万
• 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/6175550
• 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.

该应用的广泛目的是确定THC酸代表了一类不同的大麻素，据报道这些大麻素不与任何已知的大麻素受体结合。 尽管没有表现出精神活动，但它们显示了与大麻使用相关的某些药理学活动。 酸自然地以THC的代谢产物出现，因此可以在大麻使用者的组织中容易检测到。 实验模型中显示的酸的特性表明，它们可能是药用剂的候选者。 这些作用包括镇痛药和抗炎药，其滥用可能性较低，有毒副作用最少。在此提案中，将使用两种方法来回答以下问题：THC的酸代谢产物是否在父级化合物的作用中起作用。 首先，将尝试使用高特异性活性，放射性标记的酸衍生物来发现高亲和力，可饱和结合。 结构活性结合方案将旨在显示出类似于各种系统中酸能力的立体特定性和等级顺序。 其次，将研究酸的抗炎作用的可能机制，并将其与原代大麻素一起研究以寻找差异和相似性。 将进行实验，以确定它们对人细胞培养系统中细胞因子，类花生素和金属蛋白酶的影响。 在可行的地方，将检查体内相关性，以显示与上述所有研究的相关性。该提案将产生的发现可能为有关大麻医学使用的当前争议提供了可能的解决方案。 这将是通过发现大麻的活跃原理的合成类似物来实现的，该类似物将提供大麻的药物益处，而没有随附的情绪改变效果和滥用潜力。