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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", or "opioid NPS".[1][2]

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.[1] Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine.[3][4][5] 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.[6]

In the early 2020s, the substance has been recognized as emerging drugs of abuse.[7][8][9] Isotonitazene was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States beginning in 2019.[10] 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.[9] Nitazene analogs have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom[11] and New Zealand.[12]

Structure-activity relationship

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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.[13][14][15][16][17][18][19][20][21][22][23][excessive citations]

A 2019 publication[24] has shown the possibility the previously assumed binding position of the benzimidazole class,[25] 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.

Abuse

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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.[26] 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 mislabelling of nitazenes as fentanyl. While compounds from this class are sometimes incorrectly referred to as "nitazene",[27] the 4 unsubstituted compound nitazene itself is of relatively low potency and has not been reported as a designer drug, with most cases of abuse and overdose linked to more potent derivatives such as metonitazene, protonitazene, isotonitazene, etonitazepyne and etodesnitazene.

Table of benzimidazole opioids

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Chemical structure Drug name Ring substitution Analgesic potency (morphine = 1) PubChem CAS number
Desnitazene (1-diethylaminoethyl-2-benzyl-benzimidazole) hydrogen 0.1 28787 17817-67-3
Metodesnitazene (Metazene) 4-methoxy 1 26412 14030-77-4
1071546-40-1 (HCl)
Metodesnitazepyne 4-methoxy
Etodesnitazene (Etazene) 4-ethoxy 70 149797386 14030-76-3
Etodesnitazepyne 4-ethoxy 20 162623599
Etodesnitazepipne 4-ethoxy 10 162623611 102762-98-1
Protodesnitazene 4-(n-propoxy) 10 157010653 805212-21-9
Isotodesnitazene 4-isopropoxy ~75 162623708 2732926-27-9
Nitazene hydrogen 2 15327524 14030-71-8
meta-Metonitazene 3-methoxy 2
Metonitazene 4-methoxy 100 53316366 14680-51-4
Metonitazepyne 4-methoxy
Metonitazepipne 4-methoxy
N-Desethylmetonitazene 4-methoxy
Metomethazene 4-methoxy
Dimetonitazene 3,4-dimethoxy 10 162623836 95809-33-9
α-methyl-metonitazene 4-methoxy 50 162625089 806634-80-0
Metonitazene phenethyl homologue (Ethylene metonitazene) 4-methoxy 50
Etonitazene 4-ethoxy 1000-1500 13493 911-65-9
O-Desethyl-etonitazene 4-hydroxy 1 156588969 94758-81-3
N-Desethyletonitazene (NDE) 4-ethoxy 1000/1500-2000 162623580 2732926-26-8
Etonitazene 5-amino metabolite 4-ethoxy 2 13408927
Etomethazene 4-ethoxy 20 168310446 95293-25-7
Etonitazene 5-trifluoromethyl analogue (Etotriflazene)[28] 4-ethoxy 21815908
Etonitazene 5-cyano analogue (Etocyanazene) [29] 4-ethoxy 27268 15419-87-1
Etonitazene 5-acetyl analogue (Etoacetazene) [30] 4-ethoxy 25957 13406-60-5
Etonitazene 5,6-dichloro analogue (Etodicloazene) 4-ethoxy
Etonitazene N,N-dimethyl analogue 4-ethoxy 20 67089584 714190-52-0
Etonitazepyne 4-ethoxy 180-190 155804760 2785346-75-8
Etonitazepipne 4-ethoxy 190 [31] 162623834 734496-28-7
Etonitazene morpholine analogue 4-ethoxy 2 162623685 805958-08-1
Etonitazene 6-nitro isomer (iso-etonitazene) [32] 4-ethoxy 20 59799752 114160-61-1
Protonitazene 4-(n-propoxy) 200 156589001 119276-01-6
95958-84-2
Protonitazepyne 4-(n-propoxy) 180-190 168322728
Protonitazepipne 4-(n-propoxy)
N-Desethylprotonitazene 4-(n-propoxy)
Isotonitazene 4-isopropoxy 500 145721979 14188-81-9
Isotonitazepyne 4-isopropoxy 168322631
Isotonitazepipne 4-isopropoxy
N-Desethylisotonitazene 4-isopropoxy 1000-2000 162623899 2732926-24-6
Butonitazene 4-butoxy 5 156588955 95810-54-1
Isobutonitazene 4-isobutoxy
Secbutonitazene 4-secbutoxy
Etoetonitazene 4-ethoxyethoxy 50 162623504 806642-21-7
Flunitazene 4-fluoro 1 156588967 2728-91-8
Clonitazene 4-chloro 3 62528 3861-76-5
Diclonitazene 2,4-dichloro
α-carboxamido-clonitazene 4-chloro 3
Bronitazene 4-bromo 5 162623726
Nitronitazene 4-nitro
Methylnitazene (Menitazene) 4-methyl 10 162623683 95282-00-1
Ethylnitazene (Enitazene) 4-ethyl 20 162623845 114160-82-6
Propylnitazene (Pronitazene) 4-propyl 50 162623877 700342-00-3
t-Butylnitazene 4-(tert-butyl) 2 162623621 805215-64-9
Acetoxynitazene 4-acetoxy 5 162623779 102760-24-7
Methylthionitazene 4-methylthio 50 162623790 102471-37-4
Ethylthionitazene 4-ethylthio 30 162623931 102758-70-3
Etodesnitazene phenylthio analogue 4-ethoxy 1 21045 3275-92-1
Etodesnitazene phenylthio / pyrrolidine analogue 4-ethoxy 2 19846499 13451-68-8
Methylenedioxynitazene[33] 3,4-methylenedioxy
Ethyleneoxynitazene[34] fused tetrahydrofuran

See also

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References

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  1. ^ a b Pergolizzi Jr J, Raffa R, LeQuang JA, Breve F, Varrassi G (2023). "Old Drugs and New Challenges: A Narrative Review of Nitazenes". Cureus. 15 (6): e40736. doi:10.7759/cureus.40736. ISSN 2168-8184. PMC 10361140. PMID 37485167.
  2. ^ Ujváry I, Christie R, Evans-Brown M, Gallegos A, Jorge R, de Morais J, et al. (April 2021). "DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles". ACS Chemical Neuroscience. 12 (7): 1072–1092. doi:10.1021/acschemneuro.1c00037. PMID 33760580. S2CID 232356192.
  3. ^ Glatfelter GC, Vandeputte MM, Chen L, Walther D, Tsai MM, Shi L, et al. (December 2023). "Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose". Psychopharmacology. 240 (12): 2573–2584. doi:10.1007/s00213-023-06451-2. PMID 37658878.
  4. ^ Tsai MM, Chen L, Baumann MH, Canals M, Javitch JA, Lane JR, et al. (February 2024). "In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling". ACS Chemical Neuroscience. 15 (4): 854–867. doi:10.1021/acschemneuro.3c00750. PMID 38345920.
  5. ^ Kozell LB, Eshleman AJ, Wolfrum KM, Swanson TL, Bloom SH, Benware S, et al. (April 2024). "Pharmacologic Characterization of Substituted Nitazenes at μ, κ, and Δ Opioid Receptors Suggests High Potential for Toxicity". The Journal of Pharmacology and Experimental Therapeutics. 389 (2): 219–228. doi:10.1124/jpet.123.002052. PMC 11026150. PMID 38453524.
  6. ^ Montanari E, Madeo G, Pichini S, Busardò FP, Carlier J (August 2022). "Acute Intoxications and Fatalities Associated With Benzimidazole Opioid (Nitazene Analog) Use: A Systematic Review". Therapeutic Drug Monitoring. 44 (4): 494–510. doi:10.1097/FTD.0000000000000970. PMID 35149665. S2CID 246776288.
  7. ^ US patent 2935514, Hoffman K, Hunger A, "BENZMDAZOLES (sic)", published 1960-05-03, assigned to Ciba Pharmaceutical Products Inc. 
  8. ^ Drug Enforcement Administration (June 2021). "Benzimidazole Opioids" (PDF). Retrieved 6 January 2022.
  9. ^ a b Walton SE, Krotulski AJ, Logan BK (March 2022). "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. doi:10.1093/jat/bkab117. PMC 8935987. PMID 34792157.
  10. ^ European Monitoring Centre for Drugs Drug Addiction (2020-11-13). "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)". European Monitoring Centre for Drugs and Drug Addiction. Publications Office of the European Union. doi:10.2810/107576. ISBN 9789294974952. Retrieved 9 May 2022.
  11. ^ Lanes R. "PHILTRE Annual Report April 2022 - March 2023" (PDF). WEDINOS. Retrieved 1 July 2024.
  12. ^ "Potent opioid found in fake diazepam". The Level NZ. April 19, 2024. Retrieved 1 July 2024.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.
  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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. ISBN 9780444533234. PMID 5319798.
  26. ^ Homer A, Johal N (11 December 2023). "Street drugs stronger than heroin linked to 54 deaths in UK". BBC News.
  27. ^ Rising imports of potent drug nitazene raises concern. Australian Federal Police, 5 May 2024
  28. ^ Tonelli M, Cichero E, Mahmoud AM, Rabbito A, Tasso B, Fossa P, et al. (December 2018). "Exploring the effectiveness of novel benzimidazoles as CB2 ligands: synthesis, biological evaluation, molecular docking studies and ADMET prediction". MedChemComm. 9 (12): 2045–2054. doi:10.1039/c8md00461g. PMC 6301267. PMID 30647880.
  29. ^ Lecolier S, Trouiller G (1967). "Nouveaux benzimidazoles doués d'activité morphinique" [New benzimidazoles with opioid activity.]. Chim. Ther. (in French). 2: 16–24.
  30. ^ "A review of the evidence on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids" (PDF). Advisory Council on the Misuse of Drugs. UK. July 2022.
  31. ^ Vandeputte MM, Verougstraete N, Walther D, Glatfelter GC, Malfliet J, Baumann MH, et al. (June 2022). "First identification, chemical analysis and pharmacological characterization of N-piperidinyl etonitazene (etonitazepipne), a recent addition to the 2-benzylbenzimidazole opioid subclass". Archives of Toxicology. 96 (6): 1865–1880. Bibcode:2022ArTox..96.1865V. doi:10.1007/s00204-022-03294-2. hdl:1854/LU-8751259. PMID 35449307.
  32. ^ Kanamori T, Okada Y, Segawa H, Yamamuro T, Kuwayama K, Tsujikawa K, et al. (November 2022). "Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers". Drug Testing and Analysis. 15 (4): 449–457. doi:10.1002/dta.3415. PMID 36437623. S2CID 254042990.
  33. ^ "Fourth addendum to ACMD report on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids" (PDF). Advisory Council on the Misuse of Drugs. 5 April 2024.
  34. ^ "Third addendum to ACMD report on the use and harms of 2-benzyl benzimidazole ('nitazene') and piperidine benzimidazolone ('brorphine-like') opioids" (PDF). Advisory Council on the Misuse of Drugs. 15 December 2023.
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