List of benzimidazole opioids

From Wikipedia, the free encyclopedia

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, and have recently been recognized as emerging drugs of abuse.[1][2][3] 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.[4] Previously known nitazene analogs such as metonitazine and , as well as novel nitazenes not previously patented, have since been discovered in toxicologic samples during forensic investigations.[3]

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.[5][6][7][8][9][10][11][12][13][14][15][16][17]

A 2019 publication[18] has shown the possibility the previously assumed binding position of the benzimidazole class,[19] 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
Metodesnitazene structure.png Metodesnitazene (Metazene) 4-methoxy 1 26412 14030-77-4
1071546-40-1 (HCl)
Etazene.svg Etodesnitazene (Etazene) 4-ethoxy 70 149797386
Pyrrolidine-etodesnitazene structure.png Etodesnitazene pyrrolidine analogue 4-ethoxy 20
Piperidine-etodesnitazene structure.png Etodesnitazene piperidine analogue 4-ethoxy 10
Protodesnitazene structure.png Protodesnitazene 4-(n-propoxy) 10
Isotodesnitazene structure.png Isotodesnitazene 4-isopropoxy ~75
Nitazene structure.png Nitazene hydrogen 2 15327524
Meta-metonitazene structure.png meta-Metonitazene 3-methoxy 2
Metonitazene.png Metonitazene 4-methoxy 100 53316366 14680-51-4
Dimetonitazene structure.png Dimetonitazene 3,4-dimethoxy 10
Alpha-methyl-metonitazene structure.png α-methyl-metonitazene 4-methoxy 50
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-Desmethyl-etonitazene 4-hydroxy 1 94758-81-3
5-Amino-etonitazene structure.png Etonitazene 5-amino metabolite 4-ethoxy 2 13408927
Dimethyl-etonitazene structure.png Etonitazene N,N-dimethyl analogue 4-ethoxy 20
Etonitazepyne structure.png Etonitazepyne 4-ethoxy
Piperidine-etonitazene structure.png Etonitazepipne 4-ethoxy 100
Morpholine-etonitazene structure.png Etonitazene morpholine analogue 4-ethoxy 2
6-Nitro-etonitazene structure.png Etonitazene 6-nitro isomer 4-ethoxy 20
Protonitazene structure.png Protonitazene 4-(n-propoxy) 200 119276-01-6
Isotonitazene structure.png Isotonitazene 4-isopropoxy 500 145721979 14188-81-9
N-desethyl-isotonitazene structure.png N-desethyl-isotonitazene 4-isopropoxy ~1000
Butonitazene structure.png Butonitazene 4-butoxy 5 95810-54-1
Etoetonitazene structure.png Etoetonitazene 4-ethoxyethoxy 50
Fluonitazene structure.png Fluonitazene 4-fluoro 1 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
Methylnitazene structure.png Methylnitazene 4-methyl 10
Ethylnitazene structure.png Ethylnitazene 4-ethyl 20
Propylnitazene structure.png Propylnitazene 4-propyl 50
Tbutylnitazene structure.png t-Butylnitazene 4-(tert-butyl) 2
Acetoxynitazene structure.png Acetoxynitazene 4-acetoxy 5
Methylthionitazene structure.png Methylthionitazene 4-methylthio 50
Ethylthionitazene structure.png Ethylthionitazene 4-ethylthio 30
Phenylthio-etazene structure.png Etodesnitazene phenylthiol analogue 4-ethoxy 1 21045
Phenylthio-etazene-pyrrolidine structure.png Etodesnitazene phenylthiol / pyrrolidine analogue 4-ethoxy 2 19846499

See also[]

References[]

  1. ^ Hoffmann, Karl; Hunger, Alfred (May 3, 1960). "Benzimidazoles" (PDF). United States Patent Office. 2, 935, 514.
  2. ^ Drug Enforcement Administration (June 2021). "Benzimidazole Opioids" (PDF). Retrieved January 2022. {{cite web}}: Check date values in: |access-date= (help)CS1 maint: url-status (link)
  3. ^ a b 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.
  4. ^ 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)
  5. ^ US 2944062, Hoffman K, Hunger A, "Certain Alpha (1-diethylaminoethyl (2), Alpha Aryl Acetamides", issued 5 July 1960, assigned to Ciba Pharma Products Inc. 
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
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  15. ^ 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.
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  18. ^ 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.
  19. ^ 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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