Abstract
N-Benzylphenethylamines are novel psychedelic substances increasingly used for research, diagnostic, or recreational purposes. To date, only a few metabolism studies have been conducted for N-2-methoxybenzylated compounds (NBOMes). Thus, the available 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) metabolism data are limited. Herein, we investigated the metabolic profile of 25CN-NBOMe in vivo in rats and in vitro in Cunninghamella elegans (C. elegans) mycelium and human liver microsomes. Phase I and phase II metabolites were first detected in an untargeted screening, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification of the most abundant metabolites by comparison with in-house synthesized reference materials. The major metabolic pathways described within this study (mono- and bis-O-demethylation, hydroxylation at different positions, and combinations thereof, followed by the glucuronidation, sulfation, and/or N-acetylation of primary metabolites) generally correspond to the results of previously reported metabolism of several other NBOMes. The cyano functional group was either hydrolyzed to the respective amide or carboxylic acid or remained untouched. Differences between species should be taken into account in studies of the metabolism of novel substances.
Highlights
2,5-Dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) is a novel psychoactive substance (NPS) belonging to the extensive N-2-methoxybenzyl (NBOMe) family, the structure of which emerges from the renowned 2,5-dimethoxyphenethylamines functionalized at the 4-position (2C-X)
Efforts in the pursuit of novel diagnostic, therapeutic, and research tools resulted in several notable implementations of N-benzylphenethylamines (NBPEAs), such as utilization of 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethan-1-amine (25BNBOMe) as a positron emission tomography (PET) radiolabeled tracer known as [11C]Cimbi36, which has been used for visualization and quantification of serotonin 2A (5-HT2A)
Human liver microsomes, and C. elegans culture medium samples were separated using reversed-phase high-performance liquid chromatography (RP HPLC), and both high-resolution mass spectrometry (HR-MS) only and high-resolution tandem mass spectrometry (HR-MS/MS) measurements were performed by a triple quadrupole time of flight instrument. 25CN-NBOMe phase I and II metabolites were identified based on the precursor ion exact masses (PM) and most abundant fragment ions (FI) in HR-MS/MS
Summary
2,5-Dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) is a novel psychoactive substance (NPS) belonging to the extensive N-2-methoxybenzyl (NBOMe) family, the structure of which emerges from the renowned 2,5-dimethoxyphenethylamines functionalized at the 4-position (2C-X). The unprecedented and intriguing discovery that benzylation of the aminic nitrogen of 2C-X can lead to potently biologically active compounds [1] opened a broad scene for expansive, hitherto unexplored realms in the world of psychoactive drugs, and inevitably prompted comprehensive research endeavors investigating plethora analogs. Some of them materialized, flooding the NPS market since 2010 [7,8], and NBPEAs are well-established street drugs at many places around the world [9]. Due to their current potential uses in many domains of interest, pharmacological and toxicological characterizations of NBPEAs, as well as an understanding of their metabolism, are necessary
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