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Characterization of rat liver microsomal metabolites of AM‐630, a potent cannabinoid receptor antagonist, by high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry
Author(s) -
Zhang Qiang,
Ma Peng,
Wang Weiqun,
Cole Richard B.,
Wang Guangdi
Publication year - 2004
Publication title -
journal of mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 121
eISSN - 1096-9888
pISSN - 1076-5174
DOI - 10.1002/jms.640
Subject(s) - chemistry , hydroxylation , morpholine , tandem mass spectrometry , metabolic pathway , metabolite , demethylation , stereochemistry , microsome , electrospray ionization , ring (chemistry) , chromatography , mass spectrometry , metabolism , organic chemistry , biochemistry , in vitro , enzyme , gene expression , dna methylation , gene
The in vitro metabolism of AM‐630 was studied by high‐performance liquid chromatography coupled with tandem mass spectrometry. AM‐630 is an aminoalkylindole analogue that behaves primarily as a potent CB2‐selective antagonist. In this study, 17 metabolic products were identified that resulted from the incubation of AM‐630 in rat liver microsome preparations. Six metabolic pathways were proposed to account for all detected metabolites: (1) o ‐demethylation of the methoxyphenyl group, (2) morpholinyl ring opening, (3) hydroxylation on the methoxy/hydroxyl phenyl ring, (4) hydroxylation on the indole ring, (5) hydroxylation on the morpholine ring and (6) loss of the morpholine ring leading to metabolites containing either a hydroxylated or a carboxylated alkyl terminal. Three metabolites were identified as morpholinyl ring‐opening products: M1, M6 and M13. Six metabolites (M2–M5, M7 and M8) were proposed to be the products of o ‐demethylation, hydroxylation on the methoxyphenyl group or the morpholinyl ring, dehydration following morpholinyl ring monohydroxylation, or a combination of the above metabolic pathways. The remaining eight metabolites were attributed to a pathway involving the loss of the morpholine ring at various points during the metabolic processes. Copyright © 2004 John Wiley & Sons, Ltd.