Marijuana is one of the most widely abused drugs and its use has recently resurged. Our understanding of its pharmacology and physiological effects, however, remains limited. The active components of marijuana produce various central nervous system-mediated effects. Recent advances in cannabis study have led to the identification of the cannabinoid receptors, the endogenous ligands, and a number os 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 pharmacokinetic 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 newly developed cannabinoid agonists and antagonists has not been studied in detail. The goal of this project is to establish the biotransformation pathways of the recently found cannabinoid agonists have not been studied in detail. The goal of this project is to establish the biotransformation pathways of the recently found cannabinoid agonists and antagonists for the central cannabinoid receptor and to gather initial information on the receptor binding activities of the metabolites. Based on our current knowledge that several metabolites of delta9- tetrahydrocannabinol are potent cannabimimetic compounds, it is hypothesized that certain metabolites of the recently found agonists and antagonists may also exhibit cannabinoid activities. To test that hypothesis, we propose to first develop a hyphenated tandem mass spectrometric (MS/MS) method in which high performance liquid chromatography (HPLC) will be directly coupled to MS/MS through modern ionization methods, i.e., electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI). Next, we seek to identify the in vitro and in vivo metabolites of representative cannabimimetic compounds using Sprague-Dawley rats. The results obtained in metabolism studies will then be used to evaluated the cannabinoid receptor binding activities of the metabolites. The proposed research will yield valuable information on the phase I and phase II metabolic profiles of cannabinoid agonists and antagonists. The metabolites if determined in this study to exhibit high CB1 binding affinities, shall be further examined in functional assays such as mouse vas deferens (MVD) in later studies. Implementation of this project will greatly help the P.I. and the co-investigator to obtain valuable results, to involve minority undergraduate students in research, and to seek additional funding for furthering the study in the area of drugs and abuse.
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