NON PSYCHOACTIVE CANNABINOIDS WITH THERAPEUTIC POTENTIAL

本申请的广泛目标是确定THC酸代表一类不同的大麻素，据报道其不与任何已知的大麻素受体结合。 虽然没有显示出精神活性，但它们显示出与使用大麻有关的某些药理活性。 这些酸自然地作为THC的代谢物存在，因此可以在大麻使用者的组织中容易地检测到。 在实验模型中显示的酸的性质表明，它们可能是感兴趣的候选药物。 这些包括作为镇痛药和镇静剂的作用，滥用的可能性低，毒副作用最小。在本提案中，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，将尝试使用高比活度、放射性标记的酸衍生物来发现大麻素酸的高亲和力、可饱和的结合位点。 将包括的结构-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等级顺序。 第二，将研究酸的抑制作用的可能机制，并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、类花生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。这项提案将产生的调查结果可能会为目前关于大麻医疗用途的争议提供一个可能的解决方案。 这将通过发现大麻的活性成分THC的合成类似物来实现，这将提供大麻的药用益处，而不会伴随情绪改变作用和滥用潜力。

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.