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Report on a novel emerging class of highly potent benzimidazole NPS opioids : chemical and in vitro functional characterization of isotonitazene

(2020) DRUG TESTING AND ANALYSIS. 12(4). p.422-430
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Abstract
This paper reports on the identification and full chemical characterization of isotonitazene (N,N-diethyl-2-[5-nitro-2-({4-[(propan-2-yl)oxy]phenyl}methyl)-1H-benzimidazol-1-yl]ethan-1-amine), a potent NPS opioid and the first member of the benzimidazole class of compounds to be available on online markets. Interestingly, this compound was sold under the name etonitazene, a structural analog. Identification of isotonitazene was performed by gas chromatography mass spectrometry (GC-MS) and liquid chromatography time-of-flight mass spectrometry (LC-QTOF-MS), the latter identifying an exact-mass m/z value of 411.2398. All chromatographic data indicated the presence of a single, highly pure compound. Confirmation of the specific benzimidazole regio-isomer was performed using H-1 and C-13 NMR spectroscopy, after which the chemical characterization was finalized by recording Fourier-transform (FT-IR) spectra. A live cell-based reporter assay to assess the in vitro biological activity at the mu-opioid receptor (MOR) revealed that isotonitazene has a high potency (EC50 of 11.1 nM) and efficacy (E-max 180% of that of hydromorphone), thus confirming that this substance is a strong opioid. Isotonitazene has not been previously detected, either in powder form, or in biological fluids. The high potency and efficacy of isotonitazene, combined with the fact that this compound was being sold undiluted, represents an imminent danger to anyone aiming to use this powder.
Keywords
new psychoactive substances, synthetic opioids, isotonitazene, NPS, NPS opioids, UND VERWANDTE HETEROCYCLEN, URINE SAMPLES, CONSUMPTION, FENTANYL

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MLA
Blanckaert, Peter, et al. “Report on a Novel Emerging Class of Highly Potent Benzimidazole NPS Opioids : Chemical and in Vitro Functional Characterization of Isotonitazene.” DRUG TESTING AND ANALYSIS, vol. 12, no. 4, 2020, pp. 422–30.
APA
Blanckaert, P., Cannaert, A., Van Uytfanghe, K., Hulpia, F., Deconinck, E., Van Calenbergh, S., & Stove, C. (2020). Report on a novel emerging class of highly potent benzimidazole NPS opioids : chemical and in vitro functional characterization of isotonitazene. DRUG TESTING AND ANALYSIS, 12(4), 422–430.
Chicago author-date
Blanckaert, Peter, Annelies Cannaert, Katleen Van Uytfanghe, Fabian Hulpia, Eric Deconinck, Serge Van Calenbergh, and Christophe Stove. 2020. “Report on a Novel Emerging Class of Highly Potent Benzimidazole NPS Opioids : Chemical and in Vitro Functional Characterization of Isotonitazene.” DRUG TESTING AND ANALYSIS 12 (4): 422–30.
Chicago author-date (all authors)
Blanckaert, Peter, Annelies Cannaert, Katleen Van Uytfanghe, Fabian Hulpia, Eric Deconinck, Serge Van Calenbergh, and Christophe Stove. 2020. “Report on a Novel Emerging Class of Highly Potent Benzimidazole NPS Opioids : Chemical and in Vitro Functional Characterization of Isotonitazene.” DRUG TESTING AND ANALYSIS 12 (4): 422–430.
Vancouver
1.
Blanckaert P, Cannaert A, Van Uytfanghe K, Hulpia F, Deconinck E, Van Calenbergh S, et al. Report on a novel emerging class of highly potent benzimidazole NPS opioids : chemical and in vitro functional characterization of isotonitazene. DRUG TESTING AND ANALYSIS. 2020;12(4):422–30.
IEEE
[1]
P. Blanckaert et al., “Report on a novel emerging class of highly potent benzimidazole NPS opioids : chemical and in vitro functional characterization of isotonitazene,” DRUG TESTING AND ANALYSIS, vol. 12, no. 4, pp. 422–430, 2020.
@article{8636178,
  abstract     = {This paper reports on the identification and full chemical characterization of isotonitazene (N,N-diethyl-2-[5-nitro-2-({4-[(propan-2-yl)oxy]phenyl}methyl)-1H-benzimidazol-1-yl]ethan-1-amine), a potent NPS opioid and the first member of the benzimidazole class of compounds to be available on online markets. Interestingly, this compound was sold under the name etonitazene, a structural analog. Identification of isotonitazene was performed by gas chromatography mass spectrometry (GC-MS) and liquid chromatography time-of-flight mass spectrometry (LC-QTOF-MS), the latter identifying an exact-mass m/z value of 411.2398. All chromatographic data indicated the presence of a single, highly pure compound. Confirmation of the specific benzimidazole regio-isomer was performed using H-1 and C-13 NMR spectroscopy, after which the chemical characterization was finalized by recording Fourier-transform (FT-IR) spectra. A live cell-based reporter assay to assess the in vitro biological activity at the mu-opioid receptor (MOR) revealed that isotonitazene has a high potency (EC50 of 11.1 nM) and efficacy (E-max 180% of that of hydromorphone), thus confirming that this substance is a strong opioid. Isotonitazene has not been previously detected, either in powder form, or in biological fluids. The high potency and efficacy of isotonitazene, combined with the fact that this compound was being sold undiluted, represents an imminent danger to anyone aiming to use this powder.},
  author       = {Blanckaert, Peter and Cannaert, Annelies and Van Uytfanghe, Katleen and Hulpia, Fabian and Deconinck, Eric and Van Calenbergh, Serge and Stove, Christophe},
  issn         = {1942-7603},
  journal      = {DRUG TESTING AND ANALYSIS},
  keywords     = {new psychoactive substances,synthetic opioids,isotonitazene,NPS,NPS opioids,UND VERWANDTE HETEROCYCLEN,URINE SAMPLES,CONSUMPTION,FENTANYL},
  language     = {eng},
  number       = {4},
  pages        = {422--430},
  title        = {Report on a novel emerging class of highly potent benzimidazole NPS opioids : chemical and in vitro functional characterization of isotonitazene},
  url          = {http://dx.doi.org/10.1002/dta.2738},
  volume       = {12},
  year         = {2020},
}

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