Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of “Nitazene” 2-Benzylbenzimidazole Synthetic Opioids

Vandeputte, Marthe M.; Van Uytfanghe, Katleen; Layle, Nathan K.; St. Germaine, Danielle M.; Iula, Donna M.; Stove, Christophe P.

doi:10.1021/acschemneuro.1c00064

Cited by 161Forensic Toxicology and Drug AnalysisOpioid Use Disorder TreatmentAlkaloids: synthesis and pharmacology

Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of “Nitazene” 2-Benzylbenzimidazole Synthetic Opioids

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Vandeputte, Marthe M., Van Uytfanghe, Katleen, Layle, Nathan K., St. Germaine, Danielle M., Iula, Donna M., Stove, Christophe P.·2021·ACS Chemical Neuroscience

DOI 10.1021/acschemneuro.1c00064

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Abstract

Several 2-benzylbenzimidazole opioids (also referred to as “nitazenes”) recently emerged on the illicit market. The most frequently encountered member, isotonitazene, has been identified in multiple fatalities since its appearance in 2019. Although recent scheduling efforts targeted isotonitazene, many other analogues remain unregulated. Being structurally unrelated to fentanyl, little is known about the harm potential of these compounds. In this study, ten nitazenes and four metabolites were synthesized, analytically characterized via four different techniques, and pharmacologically evaluated using two cell-based β-arrestin2/mini-Gi recruitment assays monitoring μ-opioid receptor (MOR) activation. On the basis of absorption spectra and retention times, high-performance liquid chromatography coupled to diode-array detection (HPLC-DAD) allowed differentiation between most analogues. Time-of-flight mass spectrometry (LC-QTOF-MS) identified a fragment with m / z 100.11 for 12/14 compounds, which could serve as a basis for MS-based nitazene screening. MOR activity determination confirmed that nitazenes are generally highly active, with potencies and efficacies of several analogues exceeding that of fentanyl. Particularly relevant is the unexpected very high potency of the N -desethylisotonitazene metabolite, rivaling the potency of etonitazene and exceeding that of isotonitazene itself. Supported by its identification in fatalities, this likely has in vivo consequences. These results improve our understanding of this emerging group of opioids by laying out an analytical framework for their detection, as well as providing important new insights into their MOR activation potential.

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The presence of a nitazene analogue even at trace amounts, which could be below the cut-off for detection with NTS, may readily give rise to dangerous opioid effects in unknowing users.
“the presence of a nitazene analogue even at trace amounts, which could be below the cut-off for detection with NTS, may readily give rise to dangerous opioid effects in (unknowing) users.”
From Nitazene test strips: a laboratory evaluation (2024) · cites this paper as [7]
The Results & Discussion (page not provided) says even small quantities of nitazenes have high harm potential and calls for highly sensitive detection methods. The Introduction (page not provided) adds that these compounds may occur at very low concentrations and be missed in screening. The paper does not establish a detection cut-off for NTS or show that harmful amounts fall below it. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Etodesnitazene has a similar in vitro potency and efficacy as fentanyl.
“we found e.g. etodesnitazene to have a similar in vitro potency and efficacy as fentanyl [7, 13]”
From Nitazene test strips: a laboratory evaluation (2024) · cites this paper as [7]
Table 2 (Data and statistical analysis) shows etodesnitazene’s efficacy was close to fentanyl’s in both in vitro assays. Its EC50 values were about four to five times higher, however, indicating lower potency; the paper classifies it among compounds 2–10 times less potent than fentanyl. (LLM, conf=0.88)
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Synthesis, chemical characterization, and µ-opioid receptor activity assessment of the emerging group of nitazene new synthetic opioidsPreprint
Vandeputte, M. M., Uytfanghe, K. V., Layle, N. K., Germaine, D. S., Iula, D. M., & Stove, C. P. (2020) · doi:10.22541/au.160520665.59016513/v1
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Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers
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Navigating nitazenes: A pharmacological and toxicological overview of new synthetic opioids with a 2-benzylbenzimidazole core
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Report on a novel emerging class of highly potent benzimidazole NPS opioids: Chemical and in vitro functional characterization of isotonitazene
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When a Prophecy Comes True: Ethyleneoxynitazene as a 'Prophetic' Member of the Emerging Class of 2-Benzylbenzimidazole 'Nitazene' Synthetic Opioids
Vandeputte, M. M., Glatfelter, G. C., Walther, D. M., Ujváry, I., Iula, D. M., Baumann, M., & Stove, C. P. (2024) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2023.109969 · Cited by 1 · see citing works
Self-citation

Authors: Vandeputte, M. M., Van Uytfanghe, K., Layle, N. K., St. Germaine, D. M., Iula, D. M., & Stove, C. P.
Affiliations: Ghent University (BE)
Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent 9000, Belgium
Cayman Chemical (United States) (US)
Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, Michigan 48108, United States
Corresponding author: Stove, Christophe P.
ORCID: Vandeputte, Marthe M.
Stove, Christophe P.
Venue: ACS Chemical Neuroscience
Publisher: American Chemical Society (ACS)
Published: 2021-03-24
Volume: 12
Issue: 7
Pages: 1241-1251
ISSN: 1948-7193 (ISSN-L)
DOI: 10.1021/acschemneuro.1c00064
OpenAlex: W3135956040
Cited by: 161
References: 52
Citations by year: 2026: 29 · 2025: 47 · 2024: 31 · 2023: 22 · 2022: 24 · 2021: 8
FWCI: 13.85
Type: journal article
Language: en
Open access: green
doi.org
Licence: doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
Locations: ACS Chemical Neuroscience (publishedVersion)
PubMed (publishedVersion)
Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
Funders: Fonds Wetenschappelijk Onderzoek (3S038719)
Bijzonder Onderzoeksfonds (01J15517)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
Keywords: nitazenes, isotonitazene, etonitazene, opioid metabolites, illicit drug markets, opioid screening
MeSH terms: Analgesics, Opioid, Benzimidazoles, Chromatography, Liquid, Fentanyl

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Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of “Nitazene” 2-Benzylbenzimidazole Synthetic Opioids

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