List of benzimidazole opioids

{{Short description|none}} {{cs1 config|name-list-style=vanc|display-authors=6}} thumb|Benzimidazole core structure '''Benzimidazole opioids''' are a class of synthetic opioids that contain a benzimidazole core structure. The pain-relieving properties of these substances were discovered in the mid-1950s by the Swiss company Ciba AG. The most important subgroup are the '''nitazene''' opioids, which since 2019 have become increasingly widespread as narcotics in North America and Europe, as well as West Africa. Some other benzimidazole-containing opioids are classified separately under the '''orphine''' subgroup. There is currently no medical usage due to the high potencies of certain analogs.<ref>{{cite journal | vauthors = Montanari E, Madeo G, Pichini S, Busardò FP, Carlier J | title = Acute Intoxications and Fatalities Associated With Benzimidazole Opioid (Nitazene Analog) Use: A Systematic Review | journal = Therapeutic Drug Monitoring | volume = 44 | issue = 4 | pages = 494–510 | date = August 2022 | pmid = 35149665 | doi = 10.1097/FTD.0000000000000970 | s2cid = 246776288 }}</ref>

== History == thumb|150px|Desnitazene In 1957, the pharmaceutical research department of Ciba AG published the discovery of the (low) analgesic effect of 1-(''β''-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene).<ref name="pmid13473817">{{cite journal |author=Hunger A, Kebrle J, Rossi A, Hoffmann K |title=Synthesis of basic substituted, analgesically active benzimidazole derivatives |journal=Experientia |volume=13 |issue=10 |pages=400–1 |date=1957 |pmid=13473817 |doi=10.1007/BF02161116 |url=}}</ref> Shortly afterwards, the nitazenes were discovered in structure-activity relationship studies.<ref>{{cite patent |country=US |number=2935514 |status=patent |title=BENZMDAZOLES (sic) |pubdate=1960-05-03 |fdate=1957-09-19 |pridate=1957-09-28 |inventor = Hoffman K, Hunger A |assign1=Ciba Pharmaceutical Products Inc.}}</ref><ref name="auto">{{Cite web|last=Drug Enforcement Administration|date=June 2021|title=Benzimidazole Opioids|url=https://www.deadiversion.usdoj.gov/drug_chem_info/benzimidazole-opioids.pdf|access-date=6 January 2022}}</ref>

==Structure-activity relationship== The class of nitazene opioids is defined chemically by the presence of the benzimidazole core structure and pharmacologically by mu opioid agonist activity. The compounds are derived from the historical prototype 1-(''β''-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene). The replacement of the ''N'',''N''-dialkylamino unit by pyrrolidinyl or piperidinyl, which is found in nitazepyne and nitazepipne compounds, falls into the spectrum of designer drugs. Substitution of the benzyl for thienylmethyl, pyridylmethyl, α-napthylmethyl or styryl has a potency-reducing effect.<ref>{{cite journal | vauthors = Hunger A, Kebrle J, Rossi A, Hoffmann K | year = 1960 | title = Benzimidazole-Derivate und verwandte Heterocyclen III. Synthese von 1-Aminoalkyl-2-benzyl-nitro-benzimidazolen | url = | journal = Helv. Chim. Acta | volume = 43 | issue = | pages = 1032–1046 | doi = 10.1002/hlca.19600430412 }}</ref><ref name="pmid33760580">{{cite journal |vauthors=Ujváry I, Christie R, Evans-Brown M, Gallegos A, Jorge R, de Morais J, Sedefov R |title=DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles |journal=ACS Chem Neurosci |volume=12 |issue=7 |pages=1072–1092 |date=2021 |pmid=33760580 |doi=10.1021/acschemneuro.1c00037}}</ref> Substitution in position 4 of the benzyl affects analgesic potency in the following order: ethoxy > isopropyloxy > ''n''-propyloxy > methoxy > methylthio > H/Cl/F > hydroxy. The most potent of the known compounds contain a nitro group in position 5.<ref name="pmid33760580"/><ref>Dow LF, Abisogun AA, Berida TI, Krishnan S, Rathnayake U, Lindsley CW. The Nitazene Era: A Critical Turning Point in the Synthetic Opioid Crisis Beyond Fentanyl. ''J Med Chem''. 2026 Apr 9;69(7):7495-7506. {{doi|10.1021/acs.jmedchem.6c00696}} {{pmid|41952521}}</ref> The replacement of benzimidazole with an indole has been known from studies conducted by Ciba AG since 1963.<ref>{{cite journal | vauthors = Kebrle H, Hoffmann K | year = 1963 | title = "Synthesis of indole derivatives by substitution in the α-position." | url = | journal = Gazzetta Chimica Italiana | volume = 93 | issue = | pages = 238–243 }}</ref>

Relative analgesic activity values are derived from tests on mice and cannot be extrapolated directly to humans, though the same general activity trends apply.<ref>{{cite journal | vauthors = Gross F, Turrian H | title = [Benzimidazole derivatives with strong analgesic effects] | journal = Experientia | volume = 13 | issue = 10 | pages = 401–3 | date = October 1957 | pmid = 13473818 | doi = 10.1007/BF02161117 | s2cid = 6824038 }}</ref><ref name="Renton-2012">{{cite journal | vauthors = Renton P, Green B, Maddaford S, Rakhit S, Andrews JS | title = NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with μ-Opioid Agonist Activity | journal = ACS Medicinal Chemistry Letters | volume = 3 | issue = 3 | pages = 227–31 | date = March 2012 | pmid = 24900459 | pmc = 4025805 | doi = 10.1021/ml200268w }}</ref><ref name="Hunger-1957">{{cite journal | vauthors = Hunger A, Kebrle J, Rossi A, Hoffmann K | title = [Synthesis of analgesically active benzimidazole derivatives with basic substitutions] | journal = Experientia | volume = 13 | issue = 10 | pages = 400–1 | date = October 1957 | pmid = 13473817 | doi = 10.1007/BF02161116 | url = https://www.scribd.com/doc/78362960/Synthese-basisch-substituierter-analgetisch-wirksamer-Benzimidazol-Derivate-Synthesis-of-analgesically-active-benzimidazole-derivatives-with-basic-s | s2cid = 32179439 | trans-title = Synthesis of analgesically active benzimidazole derivatives with basic substitutions | url-access = subscription }}</ref><ref name="Rossi-1960">{{cite journal| vauthors = Rossi A, Hunger A, Kebrle J, Hoffmann K |title=Benzimidazol-Derivate und verwandte Heterocyclen. IV. Die Kondensation von o-Phenylendiamin mit α-Aryl- und γ-Aryl-acetessigester|journal=Helvetica Chimica Acta|year=1960|volume=43|issue=4|pages=1046–1056 |doi=10.1002/hlca.19600430413 |url=https://www.scribd.com/doc/78122927/Benzimidazole-Derivatives-and-Related-Hetero-Cycles-IV-the-Condensation-of-O-phenylenediamine-With-a-And-Gamma-Aryl-Acetoacetate-Helv-Chim-Acta-19|trans-title=Benzimidazole derivatives and related heterocycles IV. The condensation of o-phenylenediamine with α-aryl and γ-aryl-acetoacetate|language=de|url-access=subscription}}</ref><ref>{{cite journal| vauthors = Rossi A, Hunger A, Kebrle J, Hoffmann K |title=Benzimidazol-Derivate und verwandte Heterocyclen V. Die Kondensation von o-Phenylendiamin mit aliphatischen und alicyclischen β-Ketoestern|journal=Helvetica Chimica Acta|year=1960|volume=43|issue=5|pages=1298–1313|doi=10.1002/hlca.19600430515|url=https://www.scribd.com/doc/78122989/Benzimidazole-derivatives-and-related-heterocycles-V-The-condensation-of-o-phenylenediamine-with-aliphatic-and-alicyclic-%C3%9F-keto-esters-Helv-Chim-Ac|trans-title=Benzimidazole derivatives and related heterocycles V. The condensation of o-phenylenediamine with aliphatic and alicyclic β-keto esters|language=de|url-access=subscription}}</ref><ref>{{cite journal| vauthors = Hunger A, Kebrle J, Rossi A, Hoffmann K |title=Benzimidazol-Derivate und verwandte Heterocyclen VI. Synthese von Phenyl-[1-aminoalkyl-benzimidazolyl-(2)]-essigsäure-estern und -amiden|journal=Helvetica Chimica Acta|year=1960|volume=43|issue=6|pages=1727–1733|doi=10.1002/hlca.19600430634|url=https://www.scribd.com/doc/78122995/Benzimidazole-Derivatives-and-Related-Hetero-Cycles-VI-Synthesis-of-Phenyl-1-Aminoalkyl-benzimidazolyl-2-Acetic-Acid-Esters-and-Amides-Helv-Ch|trans-title=Benzimidazole derivatives and related Heterocycles VI. Synthesis of phenyl-[1-aminoalkyl-benzimidazolyl-(2)]-acetic acid esters and amides|language=de|url-access=subscription}}</ref><ref>{{cite journal| vauthors = Hunger A, Kebrle J, Rossi A, Hoffmann K |title=Benzimidazol-Derivate und verwandte Heterocyclen VII. Synthese neuer 2-Amino-benzimidazole|journal=Helvetica Chimica Acta|year=1961|volume=44|issue=5|pages=1273–1282|doi=10.1002/hlca.19610440513|url=https://www.scribd.com/doc/78123010/Benzimidazole-Derivatives-and-Related-Hetero-Cycles-VII-Synthesis-of-New-2-Amino-benzimidazole-Helv-Chim-Acta-1961-44-5-1273-1282|trans-title=Benzimidazole Derivatives and related Heterocycles VII. Synthesis of new 2-amino-benzimidazole|language=de|url-access=subscription}}</ref><ref>{{cite journal | vauthors = Gross F, Turrian H | title = [Benzimidazole derivatives with strong analgesic effects] | journal = Experientia | volume = 13 | issue = 10 | pages = 401–3 | date = October 1957 | pmid = 13473818 | doi = 10.1007/BF02161117 | url = https://www.scribd.com/doc/78362970/Uber-Benzimidazolderivate-mit-starker-analgetischer-Wirkung-Benzimidazole-derivatives-with-strong-analgesic-effects-%E2%80%93-F-Goss-H-Turrian-%E2%80%93-Experienti | s2cid = 6824038 | trans-title = Benzimidazole derivatives with strong analgesic effects | url-access = subscription }}</ref><ref name="Seki-1967a">{{cite journal | vauthors = Seki T, Sasajima M, Watanbe Y, Nakajima K | title = [Studies on 2-benzimidazolethiol derivatives. N. Analgesic effect and pharmacological property of 1-(2-diethylaminoethyl)-2-(p-ethoxyphenylthio)benzimidazole hydrochloride] | language = ja | journal = Yakugaku Zasshi | volume = 87 | issue = 3 | pages = 296–301 | date = March 1967 | pmid = 6069375 | doi = 10.1248/yakushi1947.87.3_296 | doi-access = free }}</ref><ref name="Seki-1967b">{{cite journal | vauthors = Seki T | title = [Studies on 2-benzimidazolethiol derivatives. V. Structure-activity relationship on analgesic action of 1-(dialkylamino-alkyl)-2-(p-ethoxyphenylthio)benzimidazole] | language = ja | journal = Yakugaku Zasshi | volume = 87 | issue = 3 | pages = 301–9 | date = March 1967 | pmid = 6069376 | doi = 10.1248/yakushi1947.87.3_301 | doi-access = free }}</ref><ref name="Seki-1969">{{cite journal | vauthors = Seki T, Watanabe Y | title = [Studies on 2-benzimidazolethiol derivatives. VI. Synthesis and analgesic effect of 1-(2-diethylaminoethyl)-2-(p-ethoxyphenylthio)-5-substituted benzimidazole] | language = ja | journal = Yakugaku Zasshi | volume = 89 | issue = 5 | pages = 617–26 | date = May 1969 | pmid = 5817995 | doi = 10.1248/yakushi1947.89.5_617 | doi-access = free }}</ref>{{excessive citations inline|date=May 2022}}

Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine.<ref>{{cite journal | vauthors = Glatfelter GC, Vandeputte MM, Chen L, Walther D, Tsai MM, Shi L, Stove CP, Baumann MH | title = Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose | journal = Psychopharmacology | volume = 240 | issue = 12 | pages = 2573–2584 | date = December 2023 | pmid = 37658878 | doi = 10.1007/s00213-023-06451-2 }}</ref><ref>{{cite journal | vauthors = Tsai MM, Chen L, Baumann MH, Canals M, Javitch JA, Lane JR, Shi L | title = In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling | journal = ACS Chemical Neuroscience | volume = 15 | issue = 4 | pages = 854–867 | date = February 2024 | pmid = 38345920 | doi = 10.1021/acschemneuro.3c00750 | pmc = 11890208 }}</ref><ref>{{cite journal | vauthors = Kozell LB, Eshleman AJ, Wolfrum KM, Swanson TL, Bloom SH, Benware S, Schmachtenberg JL, Schutzer KA, Schutzer WE, Janowsky A, Abbas AI | title = Pharmacologic Characterization of Substituted Nitazenes at ''μ'', ''κ'', and ''Δ'' Opioid Receptors Suggests High Potential for Toxicity | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 389 | issue = 2 | pages = 219–228 | date = April 2024 | pmid = 38453524 | doi = 10.1124/jpet.123.002052 | pmc = 11026150 }}</ref><ref>{{cite journal | vauthors = Kanamori T, Okada Y, Segawa H, Yamamuro T, Kuwayama K, Tsujikawa K, Iwata YT | date = Apr 2023 | title = Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers | url = | journal = Drug Test Anal | volume = 15 | issue = 4| pages = 449–457 | doi = 10.1002/dta.3415 | pmid = 36437623 }}</ref><ref>{{cite journal | vauthors = Vandeputte MM, Glatfelter GC, Walther D, Layle NK, St Germaine DM, Ujváry I, Iula DM, Baumann MH, Stove CP | year = 2024 | title = Characterization of novel nitazene recreational drugs: Insights into their risk potential from in vitro μ-opioid receptor assays and in vivo behavioral studies in mice | journal = Pharmacol Res | volume = 210 | issue = | article-number = 107503 | doi = 10.1016/j.phrs.2024.107503 | pmid = 39521025 | pmc = 11655282 }}</ref>

==Prevalence== In the early 2020s the substances were recognized as emerging drugs of abuse.<ref name="auto"/><ref name="Walton-2022">{{cite journal | vauthors = Walton SE, Krotulski AJ, Logan BK | title = A Forward-Thinking Approach to Addressing the New Synthetic Opioid 2-Benzylbenzimidazole Nitazene Analogs by Liquid Chromatography-Tandem Quadrupole Mass Spectrometry (LC-QQQ-MS) | journal = Journal of Analytical Toxicology | volume = 46 | issue = 3 | pages = 221–231 | date = March 2022 | pmid = 34792157 | pmc = 8935987 | doi = 10.1093/jat/bkab117 }}</ref> Isotonitazene was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States in March and April 2019.<ref>{{cite journal |title=Report on the risk assessment of N,N-diethyl-2- 4-(1-methylethoxy)phenyl]methyl]-5-nitro-1Hbenzimidazole- 1-ethanamine (isotonitazene) in accordance with Article 5c of Regulation (EC) No 1920/2006 (as amended). |journal=European Monitoring Centre for Drugs and Drug Addiction |date=2020-11-13 |doi=10.2810/107576 |url=https://op.europa.eu/en/publication-detail/-/publication/85c1a80f-27bf-11eb-9d7e-01aa75ed71a1 |access-date=9 May 2022 |publisher=Publications Office of the European Union|author1=European Monitoring Centre for Drugs Drug Addiction |isbn=978-92-9497-495-2 }}</ref> Previously known nitazene analogs such as metonitazene and butonitazene, as well as novel nitazenes not previously described in the scientific or patent literature, have since been discovered in toxicologic samples during forensic investigations.<ref name="Walton-2022" /> Nitazenes have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom<ref>{{Cite web |last=Lanes |first=Rick |title=PHILTRE Annual Report April 2022 - March 2023 |url=https://www.wedinos.org/resources/downloads/Annual-Report-22-23-English.pdf |access-date=1 July 2024 |website=WEDINOS}}</ref> and New Zealand.<ref>{{Cite web |date=April 19, 2024 |title=Potent opioid found in fake diazepam |url=https://thelevel.org.nz/news-and-stories/potent-opioid-found-in-fake-diazepam |access-date=1 July 2024 |website=The Level NZ}}</ref>

In the UK, abuse of nitazene analogues emerged in 2023 as an important cause of drug-overdose death, with it being linked to 54 deaths over a 6-month period. Most of the deaths have occurred outside London, the source of supply is thought to be by post from laboratories in China, and some of the deaths have been associated by the mislabeling of nitazenes as fentanyl.<ref>{{cite news |date=11 December 2023 |title=Street drugs stronger than heroin linked to 54 deaths in UK |url=https://www.bbc.co.uk/news/uk-67589364 |work=BBC News |vauthors=Homer A, Johal N}}</ref>

Media reports frequently refer to nitazene class opioids simply as "nitazene",<ref>[https://www.news.com.au/national/nsw-act/crime/australian-first-man-accused-of-supplying-supercharged-opioid-vapes/news-story/26454594c8056904af8580f51bcfa350 Hedgman A. Australian first: Man accused of supplying supercharged opioid vapes. News.com.au, 6 August 2025]</ref> but nitazene itself is only around the same potency as morphine and has only rarely been identified as having been sold as a recreational drug. References to "nitazene" in the context of drug overdoses or police seizures almost invariably refer instead to one of the more potent analogues, but these are generally regarded as broadly interchangable, and initial reports often do not identify the particular compound involved. Most cases of abuse and overdose are linked to potent derivatives such as metonitazene, protonitazene, isotonitazene, etonitazepyne, and etodesnitazene.

==Table of "nitazene" group of benzimidazole opioids==

{{Sticky}} {| class="wikitable sticky-header sortable" ! Structure ! Name ! Ring sub. ! Analgesic potency (morphine = 1) ! PubChem ! CAS # |- |140px |Desnitazene (1-diethylaminoethyl-2-benzyl-benzimidazole) |hydrogen |0.1 |[https://pubchem.ncbi.nlm.nih.gov/compound/28787 28787] |17817-67-3 |- |140px |Metodesnitazene (Metazene) |4-methoxy |1 |[https://pubchem.ncbi.nlm.nih.gov/compound/26412 26412] |14030-77-4<br />1071546-40-1 (HCl) |- |140px |Metodesnitazepyne |4-methoxy | | | |- |140px|class=skin-invert |Etodesnitazene (Etazene) |4-ethoxy |70 |[https://pubchem.ncbi.nlm.nih.gov/compound/149797386 149797386] |14030-76-3 |- |140px |Etodesnitazepyne |4-ethoxy |20 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623599 162623599] | |- |140px |Etodesnitazepipne |4-ethoxy |10 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623611 162623611] |102762-98-1 |- |140px |Protodesnitazene |4-(n-propoxy) |10 |[https://pubchem.ncbi.nlm.nih.gov/compound/157010653 157010653] |805212-21-9 |- |140px |Isotodesnitazene |4-isopropoxy | data-sort-value = 75|>75 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623708 162623708] |2732926-27-9 |- |140px |Butodesnitazene |4-butoxy | | | |- |140px |Desnitroclonitazene |4-chloro | |[https://pubchem.ncbi.nlm.nih.gov/compound/45590863 45590863] | |- |140px |Nitazene<ref>{{Cite web|url=https://www.wsj.com/health/healthcare/nitazenes-opioid-drug-crisis-ded1a3b9|title=Stronger Than Fentanyl: A Drug You've Never Heard of Is Killing Hundreds Every Year|first=Sune Engel Rasmussen and Ming Li | Photographs by Mary Turner for|last=WSJ|website=WSJ}}</ref> |hydrogen |2 |[https://pubchem.ncbi.nlm.nih.gov/compound/15327524 15327524] |14030-71-8 |- |140px |Thenylnitazene |hydrogen (with thiophene ring) |1 | | |- |150px |Ethylene nitazene |hydrogen |0.5 |[https://pubchem.ncbi.nlm.nih.gov/compound/15327525 15327525] |194537-85-4 |- |140px |''meta''-Metonitazene |3-methoxy |2 | |96168-49-9 |- |140px|class=skin-invert |Metonitazene |4-methoxy |100 |[https://pubchem.ncbi.nlm.nih.gov/compound/53316366 53316366] |14680-51-4 |- |140px |Metonitazepyne |4-methoxy | | |3053113-16-6 |- |140px |Metonitazepipne |4-methoxy | | | |- |140px |N-Desethylmetonitazene |4-methoxy | | | |- |140px |Metomethazene |4-methoxy | | |95138-58-2 |- |140px |Dimetonitazene |3,4-dimethoxy |10 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623836 162623836] |95809-33-9 |- |140px |2-Fluorometonitazene |2-fluoro-4-methoxy | | | |- |140px |α'-Methylmetonitazene |4-methoxy |50 |[https://pubchem.ncbi.nlm.nih.gov/compound/162625089 162625089] |806634-80-0 |- |140px |α'-Methyletonitazene |4-ethoxy | | | |- |140px |α'-hydroxy-etonitazene (EA-5270) |4-ethoxy | |[https://pubchem.ncbi.nlm.nih.gov/compound/21815907 21815907] | |- |150px |Metonitazene phenethyl homologue (Ethylene metonitazene) |4-methoxy |50 | | |- |160px |Ethylene etonitazene |4-ethoxy | | | |- |140px|class=skin-invert |Etonitazene |4-ethoxy | data-sort-value = 1250 |1000-1500 |[https://pubchem.ncbi.nlm.nih.gov/compound/13493 13493] |911-65-9 |- |140px |4'-hydroxy-nitazene, (AKA 4'-OH-nitazene, O-desethyl-etonitazene, O-desalkyl isotonitazene)

(Shared metabolite of many nitazenes<ref>{{Cite journal |last=Walton |first=Sara E. |last2=Krotulski |first2=Alex J. |last3=Logan |first3=Barry K. |date=2022-03-21 |title=A Forward-Thinking Approach to Addressing the New Synthetic Opioid 2-Benzylbenzimidazole Nitazene Analogs by Liquid Chromatography-Tandem Quadrupole Mass Spectrometry (LC-QQQ-MS) |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC8935987/ |journal=Journal of Analytical Toxicology |volume=46 |issue=3 |pages=221–231 |doi=10.1093/jat/bkab117 |issn=1945-2403 |pmc=8935987 |pmid=34792157 |quote=4ʹ-Hydroxy nitazene is a universal metabolite of nitazene analogs containing the 5-nitro group, N,N-diethylamine and an associated phenyl ether. [...] the identification of this metabolite in the absence of a parent drug could be indicative of the ingestion of any member of the series with the above common structural features.}}</ref><ref name=":0">{{Cite journal |last=Vandeputte |first=Marthe M. |last2=Van Uytfanghe |first2=Katleen |last3=Layle |first3=Nathan K. |last4=St. Germaine |first4=Danielle M. |last5=Iula |first5=Donna M. |last6=Stove |first6=Christophe P. |date=2021-04-07 |title=Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of “Nitazene” 2-Benzylbenzimidazole Synthetic Opioids |url=https://pubs.acs.org/doi/10.1021/acschemneuro.1c00064 |journal=ACS Chemical Neuroscience |language=en |volume=12 |issue=7 |pages=1241–1251 |doi=10.1021/acschemneuro.1c00064 |issn=1948-7193 |quote=the 4′-OH-metabolite is expected to be a common in vivo metabolite for several of the herein evaluated 2-benzylbenzimidazoles. However, with a 100-fold lower potency than isotonitazene, it is doubtful that this metabolite will significantly contribute to the overall in vivo effect of most analogues.| url-access = subscription}}</ref>) |4-hydroxy |1 <ref name=":0" /> |[https://pubchem.ncbi.nlm.nih.gov/compound/156588969 156588969] |94758-81-3 |- |140px |N-Desethyletonitazene (NDE) |4-ethoxy | data-sort-value = 1500 |1000/1500-2000 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623580 162623580] |2732926-26-8 |- |140px |Etonitazene 5-amino metabolite |4-ethoxy |2 |[https://pubchem.ncbi.nlm.nih.gov/compound/13408927 13408927] |75821-80-6 |- |140px |Etomethazene |4-ethoxy |20 |[https://pubchem.ncbi.nlm.nih.gov/compound/168310446 168310446] |95293-25-7 |- |140px |6-Methyldesnitroetonitazene (''Iso''-etomethazene) |4-ethoxy | |[https://pubchem.ncbi.nlm.nih.gov/compound/172872037 172872037] | |- |140px |Etonitazene 5-trifluoromethyl analogue (Etotriflazene)<ref>{{cite journal | vauthors = Sparatore F, Boido V, Fanelli F | year = 1968 | title = Dialchilamminoalchilbenzimidazoli d'interesse farmacologico | url = | journal = Farmaco | volume = 23 | issue = | pages = 344–59 }}</ref><ref name="Tonelli-2018">{{cite journal | vauthors = Tonelli M, Cichero E, Mahmoud AM, Rabbito A, Tasso B, Fossa P, Ligresti A | title = Exploring the effectiveness of novel benzimidazoles as CB2 ligands: synthesis, biological evaluation, molecular docking studies and ADMET prediction | journal = MedChemComm | volume = 9 | issue = 12 | pages = 2045–2054 | date = December 2018 | pmid = 30647880 | pmc = 6301267 | doi = 10.1039/c8md00461g }}</ref> |4-ethoxy | |[https://pubchem.ncbi.nlm.nih.gov/compound/21815908 21815908] |15451-92-0 |- |140px |5-Trifluoromethyl isotodesnitazene (Isototriflazene) |4-isopropoxy | | |15451-92-0 |- |140px |Etocyanozene (Etonitazene 5-cyano analogue) <ref>{{cite journal | vauthors = Lecolier S, Trouiller G | title = Nouveaux benzimidazoles doués d'activité morphinique. | trans-title = New benzimidazoles with opioid activity. | language = French | journal = Chim. Ther. | date = 1967 | volume = 2 | pages = 16–24 }}</ref> |4-ethoxy | |[https://pubchem.ncbi.nlm.nih.gov/compound/27268 27268] |15419-87-1 |- |140px |Protocyanazene |4-propoxy | | | |- |140px |Isotocyanozene |4-isopropoxy | | | |- |140px |Etoacetazene (Etonitazene 5-acetyl analogue) <ref>{{cite web | url = https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1091152/ACMD_advice_on_2-benzyl_benzimidazole_and_piperidine_benzimidazolone_opioids.pdf | title = A review of the evidence on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids. | work = Advisory Council on the Misuse of Drugs | location = UK | date = July 2022 }}</ref> |4-ethoxy | |[https://pubchem.ncbi.nlm.nih.gov/compound/25957 25957] |13406-60-5 |- |140px |Etonitazene 5,6-dichloro analogue (Etodicloazene)<ref>[https://patents.google.com/patent/US2980690A Hoffmann K, Hunger A, Rossi A. New basically substituted benzylbenzimidazoles. US2980690, 1959]</ref> |4-ethoxy | | |102476-04-0 |- |140px |Etonitazene N,N-dimethyl analogue |4-ethoxy |20 |[https://pubchem.ncbi.nlm.nih.gov/compound/67089584 67089584] |714190-52-0 |- |140px |Etonitazepyne |4-ethoxy |180-190 |[https://pubchem.ncbi.nlm.nih.gov/compound/155804760 155804760] |2785346-75-8 |- |140px | Etonitazepipne |4-ethoxy |190 <ref name="Vandeputte-2022">{{cite journal | vauthors = Vandeputte MM, Verougstraete N, Walther D, Glatfelter GC, Malfliet J, Baumann MH, Verstraete AG, Stove CP | title = First identification, chemical analysis and pharmacological characterization of N-piperidinyl etonitazene (etonitazepipne), a recent addition to the 2-benzylbenzimidazole opioid subclass | journal = Archives of Toxicology | volume = 96 | issue = 6 | pages = 1865–1880 | date = June 2022 | pmid = 35449307 | doi = 10.1007/s00204-022-03294-2 | bibcode = 2022ArTox..96.1865V | hdl = 1854/LU-8751259 | hdl-access = free }}</ref> |[https://pubchem.ncbi.nlm.nih.gov/compound/162623834 162623834] |734496-28-7 |- |140px |Etonitazene morpholine analogue |4-ethoxy |2 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623685 162623685] |805958-08-1 |- |140px |1-Ethyl pyrrolidinylmethyl N-desalkyl etonitazene |4-ethoxy | | | |- |140px |Etonitazene 6-nitro isomer (''iso''-etonitazene) <ref name="Kanamori-2022">{{cite journal | vauthors = Kanamori T, Okada Y, Segawa H, Yamamuro T, Kuwayama K, Tsujikawa K, Iwata YT | title = Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers | journal = Drug Testing and Analysis | volume = 15| issue = 4| pages = 449–457| date = November 2022 | pmid = 36437623 | doi = 10.1002/dta.3415 | s2cid = 254042990 }}</ref> |4-ethoxy |20 |[https://pubchem.ncbi.nlm.nih.gov/compound/59799752 59799752] |114160-61-1 |- |140px |Protonitazene |4-(n-propoxy) |200 |[https://pubchem.ncbi.nlm.nih.gov/compound/156589001 156589001] |119276-01-6<br />95958-84-2 |- |140px |Protonitazepyne |4-(n-propoxy) |180-190 |[https://pubchem.ncbi.nlm.nih.gov/compound/168322728 168322728] | |- |140px |Protonitazepipne |4-(n-propoxy) | | | |- |140px |N-Desethylprotonitazene |4-(n-propoxy) | |[https://pubchem.ncbi.nlm.nih.gov/compound/168310594 168310594] | |- |140px|class=skin-invert |Isotonitazene (partly metabolised to the more potent N-Desethylisotonitazene)<ref name=":0" /> |4-isopropoxy |500 |[https://pubchem.ncbi.nlm.nih.gov/compound/145721979 145721979] |14188-81-9 |- |140px |Isotonitazepyne |4-isopropoxy | |[https://pubchem.ncbi.nlm.nih.gov/compound/168322631 168322631] | |- |140px |Isotonitazepipne |4-isopropoxy | | | |- |140px |N-Desethylisotonitazene (an active metabolite of isotonitazene)<ref name=":0" /> |4-isopropoxy | data-sort-value = 1500 |1000-2000 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623899 162623899] |2732926-24-6 |- |140px |''iso''-isotonitazene |4-isopropoxy | | | |- |140px|class=skin-invert |Allonitazene |4-allyloxy | | | |- |140px|class=skin-invert |Cyprotonitazene |4-cyclopropoxy | | | |- |150px |Butonitazene |4-butoxy |5 |[https://pubchem.ncbi.nlm.nih.gov/compound/156588955 156588955] |95810-54-1 |- |140px |Isobutonitazene |4-isobutoxy | |[https://pubchem.ncbi.nlm.nih.gov/compound/168322282 168322282] | |- |140px |Secbutonitazene |4-secbutoxy | |[https://pubchem.ncbi.nlm.nih.gov/compound/168322285 168322285] | |- |160px |Etoetonitazene |4-ethoxyethoxy |50 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623504 162623504] |806642-21-7 |- |170px |MeTEG-nitazene |4-(triethylene glycol methyl ether) |3 | | |- |140px |Fluetonitazene (fluornitrazene) <ref>[https://patentscope.wipo.int/search/docs2/pct/WO2024196438/pdf/DSmid5epbe6M0IeOpY_SBCXPK9ChVZQCWXFov0cmbZA Michaelides M, et al. Fluorinated Mu-Opioid Receptor Agonists. WO 2024/196438]. Patentscope. WIPO</ref> |4-(2-fluoroethoxy) | |[https://pubchem.ncbi.nlm.nih.gov/compound/172332078 172332078] | |- |140px |N-Desethylfluornitrazene |4-(2-fluoroethoxy) | | | |- |140px |Fluetonitazepyne |4-(2-fluoroethoxy) | |[https://pubchem.ncbi.nlm.nih.gov/compound/172871918 172871918] | |- |140px |Trifluorometonitazene |4-trifluoromethoxy | | |954386-78-8 |- |140px |Flunitazene |4-fluoro |1 |[https://pubchem.ncbi.nlm.nih.gov/compound/156588967 156588967] |2728-91-8 |- |140px|class=skin-invert |Clonitazene |4-chloro |3 |[https://pubchem.ncbi.nlm.nih.gov/compound/62528 62528] |3861-76-5 |- |140px |Diclonitazene |2,4-dichloro | | | |- |140px |α'-carboxamido-clonitazene |4-chloro |3 | | |- |140px |Bronitazene |4-bromo |5 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623726 162623726] | |- |140px |Nitronitazene |4-nitro |0.2 | |101795-25-9 |- |140px |Cyanonitazene |4-cyano | | | |- |140px |Trifluoromenitazene |4-trifluoromethyl | | | |- |140px |Menitazene (Methylnitazene) |4-methyl |10 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623683 162623683] |95282-00-1 |- |140px |Ethylnitazene (Enitazene) |4-ethyl |20 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623845 162623845] |114160-82-6 |- |140px |Propylnitazene (Pronitazene) |4-propyl |50 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623877 162623877] |700342-00-3 |- |140px |t-Butylnitazene |4-(tert-butyl) |2 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623621 162623621] |805215-64-9 |- |140px |Acetoxynitazene |4-acetoxy |5 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623779 162623779] |102760-24-7 |- |140px |Methionitazene |4-methylthio |50 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623790 162623790] |102471-37-4 |- |140px |Ethylthionitazene |4-ethylthio |30 |[https://pubchem.ncbi.nlm.nih.gov/compound/162623931 162623931] |102758-70-3 |- |140px |Etodesnitazene phenylthio analogue |4-ethoxy |1 |[https://pubchem.ncbi.nlm.nih.gov/compound/21045 21045] |3275-92-1 |- |140px |Etodesnitazene phenylthio / pyrrolidine analogue |4-ethoxy |2 |[https://pubchem.ncbi.nlm.nih.gov/compound/19846499 19846499] |13451-68-8 |- |140px |Methylenedioxynitazene<ref>{{cite web | url = https://assets.publishing.service.gov.uk/media/660fb191a43d91001c3af1ae/Fourth+Addendum+on+ACMD_s+advice+on+2-benzyl+benzimidazole+and+piperidine+benzimidazolone+opioids.pdf | title = Fourth addendum to ACMD report on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids. | work = Advisory Council on the Misuse of Drugs | date = 5 April 2024 }}</ref> |3,4-methylenedioxy | | | |- |140px |Ethyleneoxynitazene<ref>{{cite web | url = https://assets.publishing.service.gov.uk/media/65800a2995bf65000d71911e/Generic_Definition_Addendum_on_ACMD_s_advice_on_2-benzyl_benzimidazole_and_piperidine_benzimidazolone_opioids__FINAL_DRAFTv4.pdf | title = Third addendum to ACMD report on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids. | work = Advisory Council on the Misuse of Drugs. | date = 15 December 2023 }}</ref> |fused tetrahydrofuran | | | |- |}

== References == {{reflist}}

Benzimidazole opioids Benzimidazole opioids Category:Benzimidazole opioids