ArticleArchives of toxicology2024
In vitro structure-activity relationships and forensic case series of emerging 2-benzylbenzimidazole 'nitazene' opioids.
Article in Archives of toxicology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Micro-QuEChERS Extraction for Broad-Spectrum LC-QQQ-MS Quantification of Nitazene Analogs in Plasma: A Validated Method With Casework Application.Drug testing and analysis · 2026Article
- Phase I metabolism of the methadone analog methiodone (IC-26) in pooled human liver microsomes and its detection in seven authentic human cases.Archives of toxicology · 2026Article
- Temporal and geographical patterns of nitazene detections in drug samples and biospecimens in the United States, 2019-2024.Addiction (Abingdon, England) · 2026Article
- Landscaping the Nitazene Scaffold to Identify Novel Mu-Opioid Receptor Modulators: From Molecular Design and Chemical Synthesis to Pharmacological Profiling.Journal of medicinal chemistry · 2026Article
- Novel 2-Benzylbenzimidazole Opioids: Emerging Drugs of Abuse and Pharmacological Considerations with Nitazene Analogs.Current pain and headache reports · 2026Review
- Fatal intoxications with nitazenes: postmortem findings, toxicology, and in vitro characterization at the μ-opioid receptor of six nitazene analogues.Archives of toxicology · 2026Article
- Genotoxic Potential of Metodesnitazene and Etodesnitazene: Insights with and Without S9 Metabolic Activation.International journal of molecular sciences · 2026Article
- 5-Methyl etodesnitazene human metabolism: LC-ESIAnalytical and bioanalytical chemistry · 2026Article
- Detection of Nitazenes (2-Benzylbenzimidazoles)-Novel Synthetic Opioids in Coronial Casework in Victoria, Australia.Metabolites · 2026Article
- A case of fatal intoxication with the novel synthetic opioid N-pyrrolidino protonitazene.International journal of legal medicine · 2026Article
- Human metabolism and pharmacological profiling of protonitazepyne and metonitazepyne, two highly potent nitazenes: prediction of main metabolite activity based on µ-opioid receptor docking simulations.Archives of toxicology · 2026Article
- Computational design of dynamic biosensors for emerging synthetic opioids.Nature communications · 2026Article
- Clinical and toxicological epidemiology of intoxications by new psychoactive substances in Reunion Island.International journal of emergency medicine · 2025Article
- Post-Mortem Identification and Toxicological Findings of Fluetonitazepyne and Isotonitazepyne.Drug testing and analysis · 2025Article
- Article
- The emergence of nitazenes: a new chapter in the synthetic opioid crisis.Archives of toxicology · 2025Review
- Identification of the Novel Synthetic Opioid N-Pyrrolidino Isotonitazene at an Australian Drug Checking Service.Drug testing and analysis · 2025Article
- Nitazenes: The Emergence of a Potent Synthetic Opioid Threat.Molecules (Basel, Switzerland) · 2025Review
- Pharmacology of newly identified nitazene variants reveals structural determinants of affinity, potency, selectivity for mu opioid receptors.Neuropharmacology · 2025Article
- Latest developments in small molecule analgesics: heterocyclic scaffolds I.Future medicinal chemistry · 2025Review
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8 authors.
Funding
Abstract
2-Benzylbenzimidazole 'nitazene' opioids are presenting a growing threat to public health. Although various nitazenes were previously studied, systematic comparisons of the effects of different structural modifications to the 2-benzylbenzimidazole core structure on μ-opioid receptor (MOR) activity are limited. Here, we assessed in vitro structure-activity relationships of 9 previously uncharacterized nitazenes alongside known structural analogues. Specifically, we focused on MOR activation by 'ring' substituted analogues (i.e., N-pyrrolidino and N-piperidinyl modifications), 'desnitazene' analogues (lacking the 5-nitro group), and N-desethyl analogues. The results from two in vitro MOR activation assays (β-arrestin 2 recruitment and inhibition of cAMP accumulation) showed that 'ring' modifications overall yield highly active drugs. With the exception of 4'-OH analogues (which are metabolites), N-pyrrolidino substitutions were generally more favorable for MOR activation than N-piperidine substitutions. Furthermore, removal of the 5-nitro group on the benzimidazole ring consistently caused a pronounced decrease in potency. The N-desethyl modifications showed important MOR activity, and generally resulted in a slightly lowered potency than comparator nitazenes. Intriguingly, N-desethyl isotonitazene was the exception and was consistently more potent than isotonitazene. Complementing the in vitro findings and demonstrating the high harm potential associated with many of these compounds, we describe 85 forensic cases from North America and the United Kingdom involving etodesnitazene, N-desethyl etonitazene, N-desethyl isotonitazene, N-pyrrolidino metonitazene, and N-pyrrolidino protonitazene. The low-to-sub ng/mL blood concentrations observed in most cases underscore the drugs' high potencies. Taken together, by bridging pharmacology and case data, this study may aid to increase awareness and guide legislative and public health efforts.
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