TY - JOUR T1 - In Vitro Metabolism of<em>R</em>(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor Agonist JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1077 LP - 1086 DO - 10.1124/dmd.30.10.1077 VL - 30 IS - 10 AU - Qiang Zhang AU - Peng Ma AU - Marcus Iszard AU - Richard B. Cole AU - Weiqun Wang AU - Guangdi Wang Y1 - 2002/10/01 UR - http://dmd.aspetjournals.org/content/30/10/1077.abstract N2 - R(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2, 3-de]1,4-benzoxa zinyl]-(1-naphthalenyl)methanone mesylate (WIN55212-2) is a potent cannabinoid receptor agonist that has been found to exhibit antinociceptive activity and to inhibit brain cyclooxygenase. The metabolism of WIN55212-2 has not been reported, and it is unknown whether its metabolites retain any agonist properties. In this study, in vitro metabolism of WIN55212-2 in rat liver microsome was investigated. The metabolic profile was obtained using high-performance liquid chromatography (HPLC) with UV and mass spectrometry detectors. The HPLC chromatogram revealed two major and at least six minor metabolites derived from the parent compound ([M + H]+ = m/z 427). The two major metabolites (structural isomers atm/z 461), constituting 60 to 75% of the total metabolites, were each identified as dihydrodiol metabolites resulting from the arene oxide pathway. The minor metabolites were all detected as protonated molecules, three of which appeared atm/z 477, corresponding to structural isomers of trihydroxylated parent compound; another two appeared atm/z 443, representing monohydroxylated isomers; and another was observed at m/z425, and was assigned as a dehydrogenation product. These structural assignments are based on HPLC/tandem mass spectrometry and NMR analysis. Metabolic pathways have been proposed to account for the various metabolites observed. Two major metabolites have been isolated in pure form, allowing future receptor binding studies to be conducted. The American Society for Pharmacology and Experimental Therapeutics ER -