Recent advances in cannabis study have led to the identification of the cannabinoid receptors, the endogenous ligands, and a number of synthetic agonists and antagonists. Much interest currently exists in the search for other possible endogenous ligands as well as other types of cannabinoid agonists and antagonists. Previous pharmacokinetics and metabolism studies have focused on the classical cannabinoids, and existing analytical methods either require lengthy clean-up and derivatization steps, or are inadequate in sensitivity and selectivity. The metabolism of several novel cannabinoid agonists/antagonists has not been studied in detail. Based on our current knowledge that several metabolites of delta9- tetrahydrocannabinol are potent cannabimimetic compounds, we hypothesize that certain metabolites of the recently found agonists and antagonists may also inhibit cannabimimetic properties. TO test that hypothesis, we propose to first develop a hyphenated tandem mass spectrometric (MS/MS) method based upon high performance liquid chromatography coupled to MS/MS through soft ionization techniques. Next, we will identify the in vitro and in vivo metabolites of representative cannabimimetic compounds using Sprague-Dawley rats. Major metabolites from each agonist or antagonist will then be isolated and purified. Receptor binding assays will be carried out to evaluate binding affinities of the metabolites for the central cannabinoid receptor. The proposed research will yield valuable information on the phase I and phase II metabolic profiles of the cannabinoid agonists and antagonists, as well as information on the potential in vivo cannabimimetic properties of the metabolites. Implementation of this project will greatly help the P.I. and the co-investigator to obtain valuable results, to minority students in research , and to seek additional funding for extending the cannabinoid research.
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