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Elucidation of a CGP7930 in vitro metabolite by liquid chromatography/electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry
Author(s) -
Wang Haidong,
Zhang Wenxiang,
Wang Xian
Publication year - 2016
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.7465
Subject(s) - chemistry , chromatography , electrospray ionization , mass spectrometry , quadrupole time of flight , tandem mass spectrometry , metabolite , protein mass spectrometry , electrospray , direct electron ionization liquid chromatography–mass spectrometry interface , liquid chromatography–mass spectrometry , tandem , ionization , analytical chemistry (journal) , chemical ionization , ion , organic chemistry , aerospace engineering , biochemistry , engineering
Rationale γ‐Aminobutyric acid‐B (GABA B ) receptors are widely expressed in the nervous system and have been implicated as targets for various neurological and psychiatric disorders. CGP7930 is a positive allosteric modulator of GABA B receptors. It has been demonstrated to reduce drug self‐administration and has gained increased research as a potential psychotropic treatment. Methods An in vitro metabolic system with liver microsomes of SD rats has been conducted and evaluated by probe drugs. The predominant in vitro metabolite of CGP7930 was identified and elucidated using liquid chromatography/electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry (LC/ESI‐QTOF‐MS/MS). Its structure was determined by comparing the characteristic ions of CGP7930 and those of the metabolite , based on the accurate mass measurement by MS and the fragmentation pattern obtained by MS/MS. Results We found that the main metabolic pathway of CGP7930 was via a monohydroxylation reaction and the hydroxylation site located at the terminal butyl‐carbon. The collision‐induced dissociation (CID) fragmentation of the hydroxylated metabolite underwent McLafferty rearrangement and α‐cleavage. Conclusions This work provides an understanding of the in vitro metabolism of CGP7930, which is helpful for the further study of the development of potential drug candidates targeting GABA B receptors, for the treatment of depression. The work also demonstrates that the LC/ESI‐QTOF‐MS/MS method has the advantage of possibly determining the structures of drug metabolites without the use of standards. Copyright © 2016 John Wiley & Sons, Ltd.