Characterization of rat liver microsomal metabolites of AM-630, a potent cannabinoid receptor antagonist, by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.
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.
Zhang
Qiang
Q
Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana 70125, USA.
Ma
Peng
P
Wang
Weiqun
W
Cole
Richard B
RB
Wang
Guangdi
G
D000818:Animals; D063387:Cannabinoid Receptor Antagonists; D002851:Chromatography, High Pressure Liquid; D007211:Indoles / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
D063387:Cannabinoid Receptor Antagonists; D007211:Indoles; C094023:iodopravadoline