In vitro metabolism of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist.
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 at m/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 at m/z 477, corresponding to structural isomers of trihydroxylated parent compound; another two appeared at m/z 443, representing monohydroxylated isomers; and another was observed at m/z 425, 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.
Zhang
Qiang
Q
Department of Chemistry, Xavier University of Louisiana, New Orleans 70125, Louisiana.
Ma
Peng
P
Iszard
Marcus
M
Cole
Richard B
RB
Wang
Weiqun
W
Wang
Guangdi
G
D000818:Animals; D048588:Benzoxazines; D002186:Cannabinoids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone