List of benzimidazole opioids

Benzimidazole opioids, also known as nitazenes, are a class of novel synthetic opioids. 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 [1], and have recently been recognized as emerging drugs of abuse.[2][3][4] 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.[5] 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.[4]

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.[6][7][8][9][10][11][12][13][14][15][16][17][18]

A 2019 publication[19] has shown the possibility the previously assumed binding position of the benzimidazole class,[20] 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

Chemical structure Drug name Ring substitution Analgesic potency (morphine = 1) PubChem CAS number
1-diethylaminoethyl-2-benzyl-benzimidazole hydrogen 0.1 28787
Metodesnitazene (Metazene) 4-methoxy 1 26412 14030-77-4
1071546-40-1 (HCl)
Etodesnitazene (Etazene) 4-ethoxy 70 149797386
Etodesnitazene pyrrolidine analogue 4-ethoxy 20
Etodesnitazene piperidine analogue 4-ethoxy 10
Protodesnitazene 4-(n-propoxy) 10
Isotodesnitazene 4-isopropoxy ~75
Nitazene hydrogen 2 15327524
meta-Metonitazene 3-methoxy 2
Metonitazene 4-methoxy 100 53316366 14680-51-4
Dimetonitazene 3,4-dimethoxy 10
α-methyl-metonitazene 4-methoxy 50
Metonitazene phenethyl homologue 4-methoxy 50
Etonitazene 4-ethoxy 1000 13493 911-65-9
O-Desmethyl-etonitazene 4-hydroxy 1 94758-81-3
Etonitazene 5-amino metabolite 4-ethoxy 2 13408927
Etonitazene N,N-dimethyl analogue 4-ethoxy 20
Etonitazepyne 4-ethoxy
Etonitazepipne 4-ethoxy 100
Etonitazene morpholine analogue 4-ethoxy 2
Etonitazene 6-nitro isomer 4-ethoxy 20
Protonitazene 4-(n-propoxy) 200 119276-01-6
Isotonitazene 4-isopropoxy 500 145721979 14188-81-9
N-desethyl-isotonitazene 4-isopropoxy ~1000
Butonitazene 4-butoxy 5 95810-54-1
Etoetonitazene 4-ethoxyethoxy 50
Fluonitazene 4-fluoro 1 2728-91-8
Clonitazene 4-chloro 3 62528 3861-76-5
α-carboxamido-clonitazene 4-chloro 3
Bronitazene 4-bromo 5
Methylnitazene 4-methyl 10
Ethylnitazene 4-ethyl 20
Propylnitazene 4-propyl 50
t-Butylnitazene 4-(tert-butyl) 2
Acetoxynitazene 4-acetoxy 5
Methylthionitazene 4-methylthio 50
Ethylthionitazene 4-ethylthio 30
Etodesnitazene phenylthiol analogue 4-ethoxy 1 21045
Etodesnitazene phenylthiol / pyrrolidine analogue 4-ethoxy 2 19846499

See also

References

  1. ↑ Montanari, Eva; Madeo, Graziella; Pichini, Simona; Busardò, Francesco Paolo; Carlier, Jeremy (February 9, 2022). "Acute intoxications and fatalities associated with benzimidazole opioid (nitazene analog) use: A systematic review". Therapeutic Drug Monitoring. doi:10.1097/FTD.0000000000000970.
  2. ↑ Hoffmann, Karl; Hunger, Alfred (May 3, 1960). "Benzimidazoles" (PDF). United States Patent Office. 2, 935, 514.
  3. ↑ Drug Enforcement Administration (June 2021). "Benzimidazole Opioids" (PDF). Retrieved 6 January 2022.{{cite web}}: CS1 maint: url-status (link)
  4. 1 2 Walton, Sara E; Krotulski, Alex J; Logan, Barry K (2021-11-18). "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. doi:10.1093/jat/bkab117. ISSN 0146-4760.
  5. ↑ Isotonitazine. https://www.emcdda.europa.eu/system/files/publications/13402/emcdda-Risk-Assessment-Report-on-isotonitazene.pdf: European Monitoring Centre for Drugs and Drug Addiction. 2020. pp. 7–8. ISBN 1725-4493. {{cite book}}: Check |isbn= value: length (help); External link in |location= (help)CS1 maint: location (link)
  6. ↑ US 2944062, Hoffman K, Hunger A, "Certain Alpha (1-diethylaminoethyl (2), Alpha Aryl Acetamides", issued 5 July 1960, assigned to Ciba Pharma Products Inc.
  7. ↑ Gross F, Turrian H (October 1957). "[Benzimidazole derivatives with strong analgesic effects]". Experientia. 13 (10): 401–3. doi:10.1007/BF02161117. PMID 13473818. S2CID 6824038.
  8. ↑ Vandeputte M, Van Uytfanghe K, Layle N, Germaine DS, Iula D, Stove C (12 November 2020). "Synthesis, chemical characterization, and µ-opioid receptor activity assessment of the emerging group of nitazene new synthetic opioids". Authorea. doi:10.22541/au.160520665.59016513/v1.
  9. ↑ Renton P, Green B, Maddaford S, Rakhit S, Andrews JS (March 2012). "NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with μ-Opioid Agonist Activity". ACS Medicinal Chemistry Letters. 3 (3): 227–31. doi:10.1021/ml200268w. PMC 4025805. PMID 24900459.
  10. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (October 1957). "[Synthesis of analgesically active benzimidazole derivatives with basic substitutions]" [Synthesis of analgesically active benzimidazole derivatives with basic substitutions]. Experientia. 13 (10): 400–1. doi:10.1007/BF02161116. PMID 13473817. S2CID 32179439.
  11. ↑ Rossi A, Hunger A, Kebrle J, Hoffmann K (1960). "Benzimidazol-Derivate und verwandte Heterocyclen. IV. Die Kondensation von o-Phenylendiamin mit α-Aryl- und γ-Aryl-acetessigester" [Benzimidazole derivatives and related heterocycles IV. The condensation of o-phenylenediamine with α-aryl and γ-aryl-acetoacetate]. Helvetica Chimica Acta (in German). 43 (4): 1046–1056. doi:10.1002/hlca.19600430413.
  12. ↑ Rossi A, Hunger A, Kebrle J, Hoffmann K (1960). "Benzimidazol-Derivate und verwandte Heterocyclen V. Die Kondensation von o-Phenylendiamin mit aliphatischen und alicyclischen β-Ketoestern" [Benzimidazole derivatives and related heterocycles V. The condensation of o-phenylenediamine with aliphatic and alicyclic β-keto esters]. Helvetica Chimica Acta (in German). 43 (5): 1298–1313. doi:10.1002/hlca.19600430515.
  13. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (1960). "Benzimidazol-Derivate und verwandte Heterocyclen VI. Synthese von Phenyl-[1-aminoalkyl-benzimidazolyl-(2)]-essigsäure-estern und -amiden" [Benzimidazole derivatives and related Heterocycles VI. Synthesis of phenyl-[1-aminoalkyl-benzimidazolyl-(2)]-acetic acid esters and amides]. Helvetica Chimica Acta (in German). 43 (6): 1727–1733. doi:10.1002/hlca.19600430634.
  14. ↑ Hunger A, Kebrle J, Rossi A, Hoffmann K (1961). "Benzimidazol-Derivate und verwandte Heterocyclen VII. Synthese neuer 2-Amino-benzimidazole" [Benzimidazole Derivatives and related Heterocycles VII. Synthesis of new 2-amino-benzimidazole]. Helvetica Chimica Acta (in German). 44 (5): 1273–1282. doi:10.1002/hlca.19610440513.
  15. ↑ Gross F, Turrian H (October 1957). "[Benzimidazole derivatives with strong analgesic effects]" [Benzimidazole derivatives with strong analgesic effects]. Experientia. 13 (10): 401–3. doi:10.1007/BF02161117. PMID 13473818. S2CID 6824038.
  16. ↑ Seki T, Sasajima M, Watanbe Y, Nakajima K (March 1967). "[Studies on 2-benzimidazolethiol derivatives. N. Analgesic effect and pharmacological property of 1-(2-diethylaminoethyl)-2-(p-ethoxyphenylthio)benzimidazole hydrochloride]". Yakugaku Zasshi (in Japanese). 87 (3): 296–301. doi:10.1248/yakushi1947.87.3_296. PMID 6069375.
  17. ↑ Seki T (March 1967). "[Studies on 2-benzimidazolethiol derivatives. V. Structure-activity relationship on analgesic action of 1-(dialkylamino-alkyl)-2-(p-ethoxyphenylthio)benzimidazole]". Yakugaku Zasshi (in Japanese). 87 (3): 301–9. doi:10.1248/yakushi1947.87.3_301. PMID 6069376.
  18. ↑ Seki T, Watanabe Y (May 1969). "[Studies on 2-benzimidazolethiol derivatives. VI. Synthesis and analgesic effect of 1-(2-diethylaminoethyl)-2-(p-ethoxyphenylthio)-5-substituted benzimidazole]". Yakugaku Zasshi (in Japanese). 89 (5): 617–26. doi:10.1248/yakushi1947.89.5_617. PMID 5817995.
  19. ↑ Wu Z, Hruby VJ (October 2019). "Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands". ACS Omega. 4 (17): 17457–17476. doi:10.1021/acsomega.9b02244. PMC 6812133. PMID 31656918.
  20. ↑ Beckett AH, Casy AF (February 1965). "Analgesics and their antagonists: biochemical aspects and structure-activity relationships". Progress in Medicinal Chemistry. 4: 171–218. doi:10.1016/s0079-6468(08)70169-3. PMID 5319798.
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