Identification of 2-Aminothiazolobenzazepine Metabolites in Human, Rat, Dog, and Monkey Microsomes by Ion-Molecule Reactions in Linear Quadrupole Ion Trap Mass Spectrometry
| Autor: | Hilkka I. Kenttämaa, Ryan J. Eismin, Minli Zhang, Ye Wu, Rebecca Urbanek, Doug Burdette, Hui Xiong |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Pyridines Metabolite Pharmaceutical Science Protonation Mass spectrometry Tandem mass spectrometry Mass Spectrometry Rats Sprague-Dawley chemistry.chemical_compound Dogs Pyridine Animals Humans Organic chemistry Quadrupole ion trap Ions Pharmacology Haplorhini Nitroso Combinatorial chemistry Rats Macaca fascicularis Thiazoles chemistry Microsomes Liver Ion trap Chromatography Liquid |
| Zdroj: | Drug Metabolism and Disposition. 43:358-366 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.114.061978 |
| Popis: | 2-Aminothiazolobenzazepine (2-ATBA), 7-[(1-methyl-1H-pyrazol-4-yl)methyl]-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepin-2-amine, is a D2 partial agonist that has demonstrated antipsychotic effects in a rodent in vivo efficacy model. The metabolite profile showed that 2-ATBA is mainly metabolized by oxidation. However, identification of the oxidation site(s) in the 2-aminothiazole group presents a challenge for the traditional metabolite identification methods such as liquid chromatography/mass spectrometry and NMR due to the lack of unique tandem mass spectrometry fragmentation patterns for ions with the 2-aminothiazole group oxidized at different sites and the lack of stability for purification or reference standard synthesis. We describe the characterization of the oxidized heteroatoms of the 2-aminothiazole group via gas-phase ion-molecule reactions (GPIMR) in a modified linear quadrupole ion trap mass spectrometer. The GPIMR reagents used were dimethyl disulfide, tert-butyl peroxide, and tri(dimethylamino)borane. Each reagent was introduced into the ion trap through the helium line and was allowed to react with the protonated metabolites. The ionic ion-molecule reaction products and their fragmentation profiles were compared with the profiles of the ionic ion-molecule reaction products of protonated reference compounds that had specific heteroatom functionalities. The oxidized 2-aminothiazole metabolite of 2-ATBA showed a similar GPIMR profile to that of the reference compounds with a tertiary N-oxide functionality and distinct from the profiles of the reference compounds with N-aryl hydroxylamine, nitroso, or pyridine N-oxide functionalities. This study demonstrates the feasibility of fingerprinting the chemical nature of oxidized nitrogen functional groups via GPIMR profiling for metabolite structure elucidation. |
| Databáze: | OpenAIRE |
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