NON PSYCHOACTIVE CANNABINOIDS WITH THERAPEUTIC POTENTIAL

本应用程序的广泛目标是确定四氢大麻酚酸代表大麻素的一个独特的类别，据报道，这些大麻素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，但它们显示出与大麻使用有关的某些药理活性。这些酸作为四氢大麻酚的代谢产物自然产生，因此，可以在大麻使用者的组织中很容易检测到。在实验模型中显示的酸的性质表明，它们可能是药物制剂的候选物。这些包括作为镇痛药和抗炎药的作用，滥用可能性低，毒副作用最小。在本提案中，将使用两种方法来回答四氢大麻酚的酸代谢物是否在母体化合物的作用中起作用的问题。首先，将尝试发现高亲和力，饱和结合的大麻素酸使用高比活性，放射性标记的酸衍生物。将包括的结构-活性结合协议将旨在显示立体特异性和等级顺序，类似于各种系统中的酸的效力。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。实验将确定其对细胞因子、类二十烷酸和金属蛋白酶在人细胞培养系统中的影响。在可行的情况下，将检查体内相关性，以显示上述所有研究的相关性。这项提案将产生的发现可能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。这将通过发现四氢大麻酚的合成类似物来实现，四氢大麻酚是大麻的活性成分，它将提供大麻的药用价值，而不会伴随情绪改变的影响和滥用的可能性。

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.