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Research ArticleArticle

In Vitro Metabolism ofR(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor Agonist

Qiang Zhang, Peng Ma, Marcus Iszard, Richard B. Cole, Weiqun Wang and Guangdi Wang
Drug Metabolism and Disposition October 2002, 30 (10) 1077-1086; DOI: https://doi.org/10.1124/dmd.30.10.1077
Qiang Zhang
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Peng Ma
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Marcus Iszard
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Richard B. Cole
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Weiqun Wang
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Guangdi Wang
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Abstract

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.

Footnotes

  • Financial support was provided by the National Institute on Drug Abuse through a research Grant DA07970, by National Institutes of Health-Minority Biomedical Research Support through GM08008, and by the National Science Foundation through CHE-9981948.

  • ↵1 Primary laboratory of origin: Department of Chemistry, Xavier University of Louisiana.

  • Abbreviations used are::
    AAI
    aminoalkylindole
    CP-55940
    (−)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol
    CB1
    cannabinoid receptor 1
    WIN55212-2
    R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    MS/MS
    tandem mass spectrometry
    ESI
    electrospray ionization
    COSY
    correlation spectroscopy
    amu
    atomic mass unit(s)
    • Received April 16, 2002.
    • Accepted June 25, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (10)
Drug Metabolism and Disposition
Vol. 30, Issue 10
1 Oct 2002
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Research ArticleArticle

In Vitro Metabolism ofR(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor Agonist

Qiang Zhang, Peng Ma, Marcus Iszard, Richard B. Cole, Weiqun Wang and Guangdi Wang
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1077-1086; DOI: https://doi.org/10.1124/dmd.30.10.1077

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Research ArticleArticle

In Vitro Metabolism ofR(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor Agonist

Qiang Zhang, Peng Ma, Marcus Iszard, Richard B. Cole, Weiqun Wang and Guangdi Wang
Drug Metabolism and Disposition October 1, 2002, 30 (10) 1077-1086; DOI: https://doi.org/10.1124/dmd.30.10.1077
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