Chemistry:List of benzimidazole opioids

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Benzimidazole opioids, also known as nitazenes, are a class of synthetic opioids with an unusual benzimidazole structure often referred to as opioid New Psychoactive Substances (opioid NPS).[1] First synthesized in the 1950s by CIBA Pharmaceuticals as potential analgesic medications, several substances in the class have been identified, the best known being etonitazene. Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine. While several substances in this class have found applications in research, they have never been used in clinical medicine due to their profound risk of respiratory depression and death,[2] and have recently been recognized as emerging drugs of abuse.[3][4][5] Isotonitazine was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States beginning in 2019.[6] Previously known nitazene analogs such as metonitazine and butonitazine, as well as novel nitazenes not previously patented, have since been discovered in toxicologic samples during forensic investigations.[5]

The structure-activity relationship of the drug class has been explored to a reasonable extent. The optimal substitution pattern is fairly tightly defined (i.e. N,N-diethyl on the amine nitrogen, 4-ethoxy on the benzyl ring and 5-nitro on the benzimidazole ring), but even derivatives incorporating only some of these features are still potent opioids. If a methyl or carboxamide group is added on the alpha carbon of the benzyl group, or the benzyl is replaced by 2-phenylethyl, compounds of similar activity are obtained. Relative analgesic activity values are derived from tests on mice and cannot be extrapolated directly to humans, though the same general activity trends apply.[7][8][9][10][11][12][13][14][15][16][17][18][19][excessive citations]

A 2019 publication[20] has shown the possibility the previously assumed binding position of the benzimidazole class,[21] acting as a semi-rigid fentanyl analogue may be incorrect. Based on a large scale analysis of known opioid receptor ligands a template was created through manual overlaying and alignment which has identified several mu-specific areas within the receptor. In this analysis, it is noted, etonitazene now more closely matches another, separate mu-specific region, sharing only a small area in common with the fentanyl class.

Table of benzimidazole opioids

Nitazene general.png

Chemical structure Drug name Ring substitution Analgesic potency (morphine = 1) PubChem CAS number
DEAE-BN-BI structure.png 1-diethylaminoethyl-2-benzyl-benzimidazole hydrogen 0.1 28787 17817-67-3
Metodesnitazene structure.png Metodesnitazene (Metazene) 4-methoxy 1 26412 14030-77-4
1071546-40-1 (HCl)
Etazene.svg Etodesnitazene (Etazene) 4-ethoxy 70 149797386 14030-76-3
Pyrrolidine-etodesnitazene structure.png Etodesnitazene pyrrolidine analogue 4-ethoxy 20 162623599
Piperidine-etodesnitazene structure.png Etodesnitazene piperidine analogue 4-ethoxy 10 162623611 102762-98-1
Protodesnitazene structure.png Protodesnitazene 4-(n-propoxy) 10 157010653 805212-21-9
Isotodesnitazene structure.png Isotodesnitazene 4-isopropoxy ~75 162623708 2732926-27-9
Nitazene structure.png Nitazene hydrogen 2 15327524
Meta-metonitazene structure.png meta-Metonitazene 3-methoxy 2
Metonitazene.svg Metonitazene 4-methoxy 100 53316366 14680-51-4
Metonitazepyne structure.png Metonitazepyne 4-methoxy
Dimetonitazene structure.png Dimetonitazene 3,4-dimethoxy 10 162623836
Alpha-methyl-metonitazene structure.png α-methyl-metonitazene 4-methoxy 50 162625089 806634-80-0
Phenethyl-metonitazene structure.png Metonitazene phenethyl homologue 4-methoxy 50
Etonitazene.svg Etonitazene 4-ethoxy 1000 13493 911-65-9
O-desmethyl-etonitazene structure.png O-Desethyl-etonitazene 4-hydroxy 1 156588969 94758-81-3
N-desethyletonitazene structure.png N-Desethyl-etonitazene 4-ethoxy 162623580 2732926-26-8
5-Amino-etonitazene structure.png Etonitazene 5-amino metabolite 4-ethoxy 2 13408927
Etomethazene structure.png Etomethazene 4-ethoxy
Etotriflazene structure.png Etonitazene 5-trifluoromethyl analogue[22] 4-ethoxy 21815908
Etocyanazene structure.png Etonitazene 5-cyano analogue [23] 4-ethoxy 27268 15419-87-1
Dimethyl-etonitazene structure.png Etonitazene N,N-dimethyl analogue 4-ethoxy 20 67089584 714190-52-0
Etonitazepyne structure.png Etonitazepyne 4-ethoxy 155804760 2785346-75-8
Piperidine-etonitazene structure.png Etonitazepipne 4-ethoxy 100 162623834 734496-28-7
Morpholine-etonitazene structure.png Etonitazene morpholine analogue 4-ethoxy 2 162623685 805958-08-1
6-Nitro-etonitazene structure.png Etonitazene 6-nitro isomer (iso-etonitazene) [24] 4-ethoxy 20 59799752 114160-61-1
Protonitazene structure.png Protonitazene 4-(n-propoxy) 200 156589001 119276-01-6
95958-84-2
Isotonitazene structure.png Isotonitazene 4-isopropoxy 500 145721979 14188-81-9
N-desethyl-isotonitazene structure.png N-desethyl-isotonitazene 4-isopropoxy ~1000 162623899 2732926-24-6
Butonitazene structure.png Butonitazene 4-butoxy 5 156588955 95810-54-1
Etoetonitazene structure.png Etoetonitazene 4-ethoxyethoxy 50 162623504 806642-21-7
Fluonitazene structure.png Fluonitazene 4-fluoro 1 156588967 2728-91-8
Clonitazene Structural Formula V1.svg Clonitazene 4-chloro 3 62528 3861-76-5
Alpha-CONH2-clonitazene structure.png α-carboxamido-clonitazene 4-chloro 3
Bronitazene structure.png Bronitazene 4-bromo 5 162623726
Methylnitazene structure.png Methylnitazene (Menitazene) 4-methyl 10 162623683 95282-00-1
Ethylnitazene structure.png Ethylnitazene (Enitazene) 4-ethyl 20 162623845
Propylnitazene structure.png Propylnitazene (Pronitazene) 4-propyl 50 162623877 700342-00-3
Tbutylnitazene structure.png t-Butylnitazene 4-(tert-butyl) 2 162623621 805215-64-9
Acetoxynitazene structure.png Acetoxynitazene 4-acetoxy 5 162623779 102760-24-7
Methylthionitazene structure.png Methylthionitazene 4-methylthio 50 162623790 102471-37-4
Ethylthionitazene structure.png Ethylthionitazene 4-ethylthio 30 162623931 102758-70-3
Phenylthio-etazene structure.png Etodesnitazene phenylthio analogue 4-ethoxy 1 21045
Phenylthio-etazene-pyrrolidine structure.png Etodesnitazene phenylthio / pyrrolidine analogue 4-ethoxy 2 19846499

See also

References

  1. ↑ "DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles". ACS Chemical Neuroscience 12 (7): 1072–1092. April 2021. doi:10.1021/acschemneuro.1c00037. PMID 33760580. 
  2. ↑ "Acute Intoxications and Fatalities Associated With Benzimidazole Opioid (Nitazene Analog) Use: A Systematic Review". Therapeutic Drug Monitoring 44 (4): 494–510. August 2022. doi:10.1097/FTD.0000000000000970. PMID 35149665. 
  3. ↑ & Alfred Hunger"BENZMDAZOLES" US patent 2935514, published 1960-05-03, assigned to Ciba Pharmaceutical Products Inc.
  4. ↑ Drug Enforcement Administration (June 2021). "Benzimidazole Opioids". https://www.deadiversion.usdoj.gov/drug_chem_info/benzimidazole-opioids.pdf. 
  5. ↑ 5.0 5.1 "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 of Analytical Toxicology 46 (3): 221–231. March 2022. doi:10.1093/jat/bkab117. PMID 34792157. 
  6. ↑ European Monitoring Centre for Drugs Drug Addiction (2020-11-13). "Report on the risk assessment of N,N-diethyl-2- 4-(1-methylethoxy)phenylmethyl]-5-nitro-1Hbenzimidazole- 1-ethanamine (isotonitazene) in accordance with Article 5c of Regulation (EC) No 1920/2006 (as amended)."]. European Monitoring Centre for Drugs and Drug Addiction (Publications Office of the European Union). doi:10.2810/107576. ISBN 9789294974952. https://op.europa.eu/en/publication-detail/-/publication/85c1a80f-27bf-11eb-9d7e-01aa75ed71a1. Retrieved 9 May 2022. 
  7. ↑ Hoffman K, Hunger A, "Certain Alpha (1-diethylaminoethyl (2), Alpha Aryl Acetamides", US patent 2944062, issued 5 July 1960, assigned to Ciba Pharma Products Inc.
  8. ↑ "[Benzimidazole derivatives with strong analgesic effects]". Experientia 13 (10): 401–3. October 1957. doi:10.1007/BF02161117. PMID 13473818. 
  9. ↑ "Synthesis, chemical characterization, and µ-opioid receptor activity assessment of the emerging group of nitazene new synthetic opioids.". Authorea. 12 November 2020. doi:10.22541/au.160520665.59016513/v1. 
  10. ↑ "NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with μ-Opioid Agonist Activity". ACS Medicinal Chemistry Letters 3 (3): 227–31. March 2012. doi:10.1021/ml200268w. PMID 24900459. 
  11. ↑ "[Synthesis of analgesically active benzimidazole derivatives with basic substitutions"]. Experientia 13 (10): 400–1. October 1957. doi:10.1007/BF02161116. PMID 13473817. https://www.scribd.com/doc/78362960/Synthese-basisch-substituierter-analgetisch-wirksamer-Benzimidazol-Derivate-Synthesis-of-analgesically-active-benzimidazole-derivatives-with-basic-s. 
  12. ↑ "Benzimidazol-Derivate und verwandte Heterocyclen. IV. Die Kondensation von o-Phenylendiamin mit α-Aryl- und γ-Aryl-acetessigester" (in de). Helvetica Chimica Acta 43 (4): 1046–1056. 1960. doi:10.1002/hlca.19600430413. 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. 
  13. ↑ "Benzimidazol-Derivate und verwandte Heterocyclen V. Die Kondensation von o-Phenylendiamin mit aliphatischen und alicyclischen β-Ketoestern" (in de). Helvetica Chimica Acta 43 (5): 1298–1313. 1960. doi:10.1002/hlca.19600430515. 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. 
  14. ↑ "Benzimidazol-Derivate und verwandte Heterocyclen VI. Synthese von Phenyl-[1-aminoalkyl-benzimidazolyl-(2)-essigsäure-estern und -amiden"] (in de). Helvetica Chimica Acta 43 (6): 1727–1733. 1960. doi:10.1002/hlca.19600430634. 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. 
  15. ↑ "Benzimidazol-Derivate und verwandte Heterocyclen VII. Synthese neuer 2-Amino-benzimidazole" (in de). Helvetica Chimica Acta 44 (5): 1273–1282. 1961. doi:10.1002/hlca.19610440513. 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. 
  16. ↑ "[Benzimidazole derivatives with strong analgesic effects"]. Experientia 13 (10): 401–3. October 1957. doi:10.1007/BF02161117. PMID 13473818. 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. 
  17. ↑ "[Studies on 2-benzimidazolethiol derivatives. N. Analgesic effect and pharmacological property of 1-(2-diethylaminoethyl)-2-(p-ethoxyphenylthio)benzimidazole hydrochloride]" (in ja). Yakugaku Zasshi 87 (3): 296–301. March 1967. doi:10.1248/yakushi1947.87.3_296. PMID 6069375. 
  18. ↑ "[Studies on 2-benzimidazolethiol derivatives. V. Structure-activity relationship on analgesic action of 1-(dialkylamino-alkyl)-2-(p-ethoxyphenylthio)benzimidazole]" (in ja). Yakugaku Zasshi 87 (3): 301–9. March 1967. doi:10.1248/yakushi1947.87.3_301. PMID 6069376. 
  19. ↑ "[Studies on 2-benzimidazolethiol derivatives. VI. Synthesis and analgesic effect of 1-(2-diethylaminoethyl)-2-(p-ethoxyphenylthio)-5-substituted benzimidazole]" (in ja). Yakugaku Zasshi 89 (5): 617–26. May 1969. doi:10.1248/yakushi1947.89.5_617. PMID 5817995. 
  20. ↑ "Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands". ACS Omega 4 (17): 17457–17476. October 2019. doi:10.1021/acsomega.9b02244. PMID 31656918. 
  21. ↑ "Analgesics and their antagonists: biochemical aspects and structure-activity relationships". Progress in Medicinal Chemistry 4: 171–218. February 1965. doi:10.1016/s0079-6468(08)70169-3. ISBN 9780444533234. PMID 5319798. 
  22. ↑ "Exploring the effectiveness of novel benzimidazoles as CB2 ligands: synthesis, biological evaluation, molecular docking studies and ADMET prediction". MedChemComm 9 (12): 2045–2054. December 2018. doi:10.1039/c8md00461g. PMID 30647880. 
  23. ↑ Chimica Therapeutica 2(16): 1967.
  24. ↑ "Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers". Drug Testing and Analysis. November 2022. doi:10.1002/dta.3415. PMID 36437623. 




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