Synthesis and identification of metabolite biomarkers of 25C-NBOMe and 25I-NBOMe
Introduction
It is estimated that a total of 246 million people, or 1 out of 20 people between the ages of 15 and 64 years, used an illicit drug in 2014 according to the World Drug Report 2016. Although drug abuse may lead to many health and social problems,1 new psychoactive substances (NPS) that are produced by clandestine laboratories and purchased via the internet head shops, keep being pumped into the market with 66 new psychoactive substances firstly reported to the EU early warning system in 2017.2
The NBOMes (N-Benzyl-oxy-methyl derivatives of 2C phenylethylamines), a new group of NPS, have strong hallucinogenic effects and have been reportedly sold as a legal alternative to lysergic acid diethylamide (LSD). More than 39 NBOMes and analogues have been reported.3, 4 The most commonly abused NBOMes are 25I-NBOMe, 25C-NBOMe and 25B-NBOMe (Fig. 1), which are now scheduled as controlled substances in many countries. Ingestion of these substances can cause tachycardia, agitation, hallucination, hypertension, confusion and mydriasis.5, 6 Cases of fatal intoxication associated with the use of NBOMes have been reported around the world, e.g. in the US, Europe, and Australia.6, 7, 8
It can be challenging to detect NPS because the parent drugs are not always found in urine specimens. Metabolites can be a more suitable target and can also extend the time window of detection.
Therefore, metabolite identification studies to determine NPS biomarkers are important. There are only a few reports on NBOMe metabolism although fatal intoxication cases caused by using NBOMes have been reported in several countries. Studies on the metabolism of 25I-NBOMe and 25B-NBOMe using LC-HR-MS etc. analytical methods have been carried out by Caspar and Boumrah in 2015.9, 10 In the same year, Poklis et al. reported the identification of metabolite biomarkers of 25I-NBOMe as well as the synthesis of two major metabolites with 8 and 9 steps respectively.11 With synthetic reference standards, the metabolites with mono-demethylation of the 2,5-dimethoxyphenyl ring can now be distinguished. Since the synthetic route is long, there is need for optimization or identification of other metabolite biomarkers, which could be synthesized in fewer steps.
25C-NBOMe is one of the most abused NBOMes; to the best of our knowledge, there are no reports on the synthesis of its metabolite biomarkers. In collaboration with the National Board of Forensic Medicine of Sweden we synthesized several potential metabolites of 25C-NBOMe and 25I-NBOMe for comparison.
Section snippets
Results and discussion
Aldehyde 2 is commercially available. It can also be synthesized from compound 1 using MeI under basic conditions.12 The methylation is selective, which might be due to the acidic difference of the two phenol groups. The yield was moderate due to incomplete conversion. Henry reaction between compound 2 and nitromethane gave 3 in high yield. When a higher amount of nitromethane was used with starting material of 9, a lower yield was obtained and dialkylation side product was increased. The
Conclusion
Straightforward synthetic routes have been developed for the synthesis of potential metabolites of 25C-NBOMe and 25I-NBOMe. The yield might be improved if further optimization is carried out. Analysis of authentic urine species and human hepatocyte samples showed that 5′-desmethyl-25C-NBOMe (compound 8) and 5-OH-25C-NBOMe (compound 20a) are two metabolite biomarkers, which can be used as targets in urine analysis for 25C-NBOMe. Further study on the metabolites of 25I-NBOMe suggested that
General information
TLC was performed using 0.25 mm precoated silica-gel plates (Merck 60 F254), detection by UV-abs at 254 nm. 1H and 13C-NMR spectra were recorded on a Varian Mercury 300 MHz instrument (25 °C in CDCl3 or methanol-d4). HPLC-MS was performed on a Waters system Column: XSELECT Phenyl-Hexyl, 5 μm, 250 × 19 mm and Waters X-Bridge C-18 3.5 μm, 50 × 4.6 mm for preparative and analytical experiments respectively; Mobile phase: organic phase: acetonitrile:water 90:10, with 10 mM NH4OAc; water phase:
Acknowledgements
Financial support from the National Board of Forensic Medicine in Sweden is gratefully acknowledged.
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Cited by (5)
Synthesis of 25X-BOMes and 25X-NBOHs (X = H, I, Br) for pharmacological studies and as reference standards for forensic purposes
2021, Tetrahedron LettersCitation Excerpt :Lastly, in numerous cases - as is the case for NBOMes and NBOHs - reference standards are not marketed by brands that serve globally, which makes accessing them difficult [13]. The majority of synthetic approaches for preparing NBOMes and NBOHs start from phenethylamines (2C-X; X = H, I, Br or Cl), obtained from commercial sources [14–16]; however, it should be noted that these phenethylamines are very expensive (1.0 mg costs up to 57.5 US dollars, Sigma-Aldrich, CAS Number: 56281-37-9). In addition, the few procedures available starting from simple materials have multiple steps and low yields.
Interpol review of controlled substances 2016–2019
2020, Forensic Science International: SynergyCitation Excerpt :2-, 3-, and 4-Fluorophenmetrazines: 2017 synthesis and extensive analytical characterization of five powdered samples advertised as 3-FPM that were purchased from 5 difference internet vendors and differentiation from synthesized ortho- and para-substituted isomers, 2-FPM and 4-FPM [1020]; NBOMe Compounds: 2016 The detection of NBOMe designer drugs on blotter paper by high resolution time-of-flight mass spectrometry (TOFMS) with and without chromatography [1021]; case series: toxicity from 25B–NBOMe--a cluster of N-bomb cases [1022]; HPTLC and GC-MS analysis of 25 C NBOMe in Seized Blotters [1023]; Detection of 25C–NBOMe using LC-QTOF designer drug screen and quantitated by LC-MS-MS [1024]; identification of 2,4,6-TMPEA-NBOMe by GC-MS, GC-HRMS, GC-HRMS/MS, UHPLC/HRMS, UHPLC/HRMS/MS, and (1) H and (13) C NMR [1025]; analytical characterization of 3,4-DMA-NBOMe (1), 4-EA-NBOMe (2), 4-MMA-NBOMe (3), and 5-APB-NBOMe (4) by MS, IR spectroscopic, and NMR spectroscopic data [1026]; chemical profiling of 25I–NBOMe TLC, UV–Vis, ATR-FTIR, GC-MS and ESI-FT-ICR MS [1027]; identification of 25X-NBOMe and analogues by GC-MS [1028]; 2017 Rapid screening and analytical determination of 25B–NBOMe and 25I–NBOMe via Cyclic and Differential Pulse Voltammetry [1029]; 25B–NBOMe and 25C–NBOMe by GC-MS, LC-MS(n), and LC-HR-MS/MS [1030]; Identification and quantification of 5 different 25-NBOMes (25B–NBOMe, 25C–NBOMe, 25D-NBOMe, 25H–NBOMe, 25I–NBOMe) via LC-MS-MS [1031]; synthesis of potential metabolites of 25C–NBOMe and 25I–NBOMe [1032]; UPLC-QTOF-MS analysis of twelve 2C-X, six 2,5-dimethoxyamphetamines (DOX), and fourteen 25X-NBOMe derivatives, including two deuterated derivatives (2C–B-d(6) and 25I–NBOMe-d(9) [1033]; identification of NBOMes and the analogous 2,5-dimethoxy phenethylamine structures by voltammetric methods in blotting paper seized from the drug market [1034]; modification of solvent delay window to prevent misidentification of 25I–NBOH as 2C–I with GC-MS [1035]; 25c-nbome: Case report and literature review [1036]; comparison of nano-LC-HRMS/MS to UHPLC for detection of 3,4-DMA-NBOMe and 4-MMA-NBOMe and metabolites [1037]; 2018 square-wave voltammetry for the quantification of NBOMes and their correlates, 2,5-dimethoxy phenethylamine structures in seized blotting paper [1038]; the analysis of illicit 25X-NBOMe from over 100 seizures in Western Australia [1039]; LC-HR-MS/MS identification of the phase I and II metabolites of 4-EA-NBOMe [1040]; LC-MS-MS confirmation of 251-NBOMe [1041]; 2019 handheld NIR spectrometer for discrimination of NBOMe and NBOH drugs absorbed in blotter papers using PLS-DA and SIMCA [1042]; 2019 SPCE electrochemical method for the detection of 25I–NBOH and full differentiation between 25I–NBOH, 2C–I and 25I–NBOMe [1043]; review [1044]; review of the main methods for the analysis of NBOMe compounds for detection in seized and biological materials for forensic and clinical purposes [1045]; the fragmentation patterns of NBOMe derivatives were analyzed using LC-QTOF/MS and the spectral data was used to establish a molecular networking map for NBOMe derivatives [1046]. 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2-(4-Iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOME): A Harmful Hallucinogen Review
2020, Journal of Analytical ToxicologyNanosensor for Sensitive Detection of the New Psychedelic Drug 25I-NBOMe
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