New psychoactive substances are constantly emerging, among which ketamine analogs with the core structure of 2-amino-2-phenylcyclohexanone have attracted global attention due to their continued involvement in acute intoxications. The monitoring of these substances largely relies on the acquisition of metabolic data. However, the lack of in vitro human metabolism information for these emerging structural analogs presents significant challenges to drug control efforts. To address this challenge, we investigated the first-phase metabolism patterns of four novel ketamine structural analogs of 2-FXE [2-(ethylamino)-2-(2-fluorophenyl) cyclohexan-1-one], 2-MDCK [2-(methylamino)-2-(o-tolyl) cyclohexan-1-one], 3-DMXE [2-(ethylamino)-2-(m-tolyl) cyclohexan-1-one], and 2-DMXE [2-(ethylamino)-2-(o-tolyl) cyclohexan-1-one] utilizing human liver microsomes for the first time. Metabolites were identified using ultra-performance liquid chromatography coupled with high-resolution tandem mass spectrometry. Our findings reveal that N-dealkylation and hydroxylation are the primary metabolic reactions, alongside other notable reactions, including oxidation, reduction, and dehydration. Based on our extensive research, we propose N-dealkylation and hydroxylation metabolites as appropriate analytical markers for monitoring the consumption of these substances.

中文翻译：

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氯胺酮四种新型结构类似物 2-FXE [2-(乙氨基)-2-(2-氟苯基)环己烷-1-酮]、2-MDCK [2-(甲氨基)-2-(邻甲苯基)] 的代谢环己烷-1-酮]、3-DMXE [2-(乙氨基)-2-(间甲苯基)环己烷-1-酮]和 2-DMXE [2-(乙氨基)-2-(邻甲苯基)环己烷-1-one]，基于超高效液相色谱-高分辨率串联质谱法的人肝微粒体


新的精神活性物质不断涌现，其中以2-氨基-2-苯基环己酮为核心结构的氯胺酮类似物因其持续参与急性中毒而引起全球关注。这些物质的监测很大程度上依赖于代谢数据的获取。然而，缺乏这些新兴结构类似物的体外人体代谢信息给药物管制工作带来了重大挑战。为了应对这一挑战，我们研究了 2-FXE [2-(乙基氨基)-2-(2-氟苯基) 环己烷-1-酮]、2-MDCK [2-] 的四种新型氯胺酮结构类似物的第一相代谢模式。 (甲基氨基)-2-(邻甲苯基)环己烷-1-酮]、3-DMXE [2-(乙基氨基)-2-(间甲苯基)环己烷-1-酮]和2-DMXE [2-(乙基氨基)-2-(邻甲苯基)环己烷-1-酮]首次利用人肝微粒体。使用超高效液相色谱与高分辨率串联质谱联用来鉴定代谢物。我们的研究结果表明， N-脱烷基化和羟基化是主要的代谢反应，还有其他值得注意的反应，包括氧化、还原和脱水。基于我们广泛的研究，我们建议N-脱烷基化和羟基化代谢物作为监测这些物质消耗的适当分析标记。