Abstract
Compounds from the N-benzylphenethylamine (NBPEA) class of novel psychoactive substances are being increasingly utilized in neurobiological and clinical research, as diagnostic tools, or for recreational purposes. To understand the pharmacology, safety, or potential toxicity of these substances, elucidating their metabolic fate is therefore of the utmost interest. Several studies on NBPEA metabolism have emerged, but scarce information about substances with a tetrahydrobenzodifuran (“Fly”) moiety is available. Here, we investigated the metabolism of 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran-4-yl)-N-(2-methoxybenzyl)ethan-1-amine (2C-B-Fly-NBOMe) in three different systems: isolated human liver microsomes, Cunninghamella elegans mycelium, and in rats in vivo. Phase I and II metabolites of 2C-B-Fly-NBOMe were first detected in an untargeted screening and identified by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Several hypothesized metabolites were then synthesized as reference standards; knowledge of their fragmentation patterns was utilized for confirmation or tentative identification of isomers. Altogether, thirty-five phase I and nine phase II 2C-B-Fly-NBOMe metabolites were detected. Major detected metabolic pathways were mono- and poly-hydroxylation, O-demethylation, oxidative debromination, and to a lesser extent also N-demethoxybenzylation, followed by glucuronidation and/or N-acetylation. Differences were observed for the three used media. The highest number of metabolites and at highest concentration were found in human liver microsomes. In vivo metabolites detected from rat urine included two poly-hydroxylated metabolites found only in this media. Mycelium matrix contained several dehydrogenated, N-oxygenated, and dibrominated metabolites.
Highlights
New Psychoactive Substances (NPS) are novel analogues of already legally regulated psychoactive substances
2-(8-Bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran-4-yl)-N-(2-methoxybenzyl)ethan1-amine (2C-B-Fly-NBOMe, compound 1; Scheme 1), a substance belonging to the NBPEAs, was first reported in a 1999 poster presenting the results of a search for potent and stereoselective 5-HT2AR antagonists and its new agonists as tools for the study of 5-HT2ARmediated functions [4]
We focused on the comparison of the metabolism of 2C-B-Fly-NBOMe in human liver microsomes (HLM), in the mycelium of Cunninghamella elegans (C. elegans), and in vivo in rats
Summary
New Psychoactive Substances (NPS) are novel analogues of already legally regulated psychoactive substances. 2-(8-Bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b’]difuran-4-yl)-N-(2-methoxybenzyl)ethan1-amine (2C-B-Fly-NBOMe, compound 1; Scheme 1), a substance belonging to the NBPEAs, was first reported in a 1999 poster presenting the results of a search for potent and stereoselective 5-HT2AR antagonists and its new agonists as tools for the study of 5-HT2ARmediated functions [4]. The substitution of amine by a benzyl group with a methoxy (NBOMe) or hydroxy (NBOH) substituent in the ortho position leading to an extreme increase in potency at the 5-HT2 receptors was found to be generalizable [5,6] This scaffold was further investigated by Ralf Heim, developing and analyzing the plethora of novel Nbenzylphenethylamine analogues [7]. Compound 1 exhibits subnanomolar affinity and high activation efficacy of the 5-HT2AR in a neuronal
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