Synthetic cannabinoids (SCs) constitute one of the most rapidly expanding class of new psychoactive substances. SCs pose a health threat to the individual and to the public due to their central (psychoactive) and peripheral effects. Their pharmacology and toxicology are poorly understood, and the substances can be unexpectedly toxic and harmful. The metabolism of SCs is also relevant in clinical and forensic toxicology as SCs are excreted in urine mostly as their metabolites. Thus, SC metabolites are widely used as markers for identifying SC intake. Herein, we used human liver microsome systems to study the in vitro phase I metabolic profiling of five SCs, namely AM-694, 5F-NNEI, FUB-APINACA, MFUBINAC, and AMB-FUBINACA. The metabolites were detected and structurally elucidated by liquid chromatography-high resolution mass spectrometry. The main metabolic pathway of AM-694 (benzoyl-indole SC) is oxidative defluorination; 5F-NNEI (naphthyl-indole carboxamide SC) follows amide hydrolysis and monohydroxylation at the naphthyl moiety. However, indazole carboxamide substituted with an adamantyl group, such as FUB-APINACA, is likely to produce (isomeric) hydroxylation of the adamantyl group as the main metabolite species. For the substrates that contain ester bonds in their structure, like MFUBINAC and AMB-FUBINACA, the ester hydrolysis metabolite is predominant.

中文翻译：

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合成大麻素AM-694、5F-NNEI，FUB-APINACA，MFUBINAC和AMB-FUBINACA的体外I期代谢谱分析。

合成大麻素（SCs）是发展最快的新型精神活性物质之一。由于SC的中枢（精神活性）和外围作用，它们对个人和公众构成健康威胁。人们对其药理和毒理学知之甚少，并且这些物质可能出乎意料地有毒和有害。SC的代谢在临床和法医毒理学中也很重要，因为SC大多以代谢物的形式从尿中排出。因此，SC代谢物被广泛用作鉴定SC摄入的标志物。本文中，我们使用人肝微粒体系统研究了五个SC（即AM-694、5F-NNEI，FUB-APINACA，MFUBINAC和AMB-FUBINACA）的体外I期代谢谱。通过液相色谱-高分辨率质谱法检测代谢产物并在结构上阐明。AM-694（苯甲酰基-吲哚SC）的主要代谢途径是氧化脱氟。5F-NNEI（萘基吲哚羧酰胺SC）跟随酰胺水解并在萘基部分单羟基化。但是，被金刚烷基取代的吲唑羧酰胺，如FUB-APINACA，很可能产生金刚烷基作为主要代谢物的（异构）羟基化反应。对于结构中含有酯键的底物（例如MFUBINAC和AMB-FUBINACA），酯水解代谢物占主导地位。可能会产生金刚烷基基团的（异构）羟基化作用，这是主要的代谢物。对于结构中含有酯键的底物（例如MFUBINAC和AMB-FUBINACA），酯水解代谢物占主导地位。可能会产生金刚烷基的（异构）羟基化，这是主要的代谢物。对于结构中含有酯键的底物（例如MFUBINAC和AMB-FUBINACA），酯水解代谢物占主导地位。