Characterization of the four designer benzodiazepines clonazolam, deschloroetizolam, flubromazolam, and meclonazepam, and identification of their in vitro metabolites
Characterization of the four designer benzodiazepines clonazolam, deschloroetizolam, flubromazolam, and meclonazepam, and identification of their in vitro metabolites
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DOI：
10.1007/s11419-015-0277-6
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发表时间：
2015-07-01
影响因子：
2.2
通讯作者：
Moosmann, Bjoern
中科院分区：
文献类型：
--
作者：
Huppertz, Laura M.;Bisel, Philippe;Moosmann, Bjoern
2012年，第一个设计师苯二氮卓类药物在互联网商店中提供，作为处方苯二氮卓类药物的替代品。在这些化合物在不同的国家被列入计划后不久，新的物质如氯唑仑、去氯乙唑仑、氟溴唑仑和甲氯硝西泮开始出现。本文介绍了这四个设计师苯二氮卓类的表征，使用核磁共振光谱，气相色谱-电子电离-质谱，液相色谱-串联质谱，液相色谱-四极杆飞行时间-质谱和红外光谱。使用人肝微粒体研究了这些物质的主要体外I相代谢产物。每种化合物至少鉴别出一种单羟基化代谢产物。发现脱氯依替唑仑和氟溴唑仑的二羟基化代谢物。对于氯硝唑仑和甲氯硝西泮，观察到对应于硝基还原为胺的质荷比信号。对于所研究的任何化合物，均未观察到脱烷基化、脱卤或羧化。此外，对于氯那唑仑和甲氯硝西泮，未检测到还原和单/二羟基化组合形成的代谢产物。这些知识将有助于分析生物样品中的这些药物。
In 2012, the first designer benzodiazepines were offered in Internet shops as an alternative to prescription-only benzodiazepines. Soon after these compounds were scheduled in different countries, new substances such as clonazolam, deschloroetizolam, flubromazolam, and meclonazepam started to emerge. This article presents the characterization of these four designer benzodiazepines using nuclear magnetic resonance spectroscopy, gas chromatography-electron ionization-mass spectrometry, liquid chromatography-tandem mass spectrometry, liquid chromatography-quadrupole time-of-flight-mass spectrometry, and infrared spectroscopy. The major in vitro phase I metabolites of the substances were investigated using human liver microsomes. At least one monohydroxylated metabolite was identified for each compound. Dihydroxylated metabolites were found for deschloroetizolam and flubromazolam. For clonazolam and meclonazepam, signals at mass-to-charge ratios corresponding to the reduction of the nitro group to an amine were observed. Desalkylations, dehalogenations, or carboxylations were not observed for any of the compounds investigated. Furthermore, for clonazolam and meclonazepam, no metabolites formed by a combination of reduction and mono-/dihydroxylation were detected. This knowledge will help to analyze these drugs in biological samples.