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.
