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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.[3][1] Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine.[4][5][6][7][8] 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.[9]

In the early 2020s, the substance has been recognized as emerging drugs of abuse.[10][11][12] 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.[13] 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.[12] Nitazene analogs have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom[14] and New Zealand.[15]

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.[16][17][18][19][20][21][22][23][24][25][26][excessive citations]

A 2019 publication[27] has shown the possibility the previously assumed binding position of the benzimidazole class,[28] 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.[29] 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",[30] 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
Ethylene nitazene hydrogen 15327525
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
α-methyl-etonitazene 4-ethoxy
α-hydroxy-etonitazene 4-ethoxy 21815907
Metonitazene phenethyl homologue (Ethylene metonitazene) 4-methoxy 50
Ethylene etonitazene 4-ethoxy
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)[31] 4-ethoxy 21815908
5-Trifluoromethyl isotodesnitazene 4-isopropoxy
Etonitazene 5-cyano analogue (Etocyanazene) [32] 4-ethoxy 27268 15419-87-1
Etonitazene 5-acetyl analogue (Etoacetazene) [33] 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 [34] 162623834 734496-28-7
Etonitazene morpholine analogue 4-ethoxy 2 162623685 805958-08-1
1-Ethyl pyrrolidinylmethyl N-desalkyl etonitazene 4-ethoxy
Etonitazene 6-nitro isomer (iso-etonitazene) [35] 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
iso-isotonitazene 4-isopropoxy
Butonitazene 4-butoxy 5 156588955 95810-54-1
Isobutonitazene 4-isobutoxy 168322282
Secbutonitazene 4-secbutoxy 168322285
Etoetonitazene 4-ethoxyethoxy 50 162623504 806642-21-7
Fluornitrazene [36] 4-(2-fluoroethoxy) 172332078
Trifluorometonitazene 4-trifluoromethoxy
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
Methionitazene 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[37] 3,4-methylenedioxy
Ethyleneoxynitazene[38] 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. ^ US 2944062, Hoffman K, Hunger A, "Certain Alpha (1-diethylaminoethyl (2), Alpha Aryl Acetamides", issued 5 July 1960, assigned to Ciba Pharma Products Inc. 
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  8. ^ Vandeputte MM, Glatfelter GC, Walther D, Layle NK, St Germaine DM, Ujváry I, Iula DM, Baumann MH, Stove CP. 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. Pharmacol Res. 2024 Nov 7;210:107503. doi:10.1016/j.phrs.2024.107503 PMID 39521025
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  23. ^ 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.
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  25. ^ 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.
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  27. ^ 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.
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  29. ^ Homer A, Johal N (11 December 2023). "Street drugs stronger than heroin linked to 54 deaths in UK". BBC News.
  30. ^ Rising imports of potent drug nitazene raises concern. Australian Federal Police, 5 May 2024
  31. ^ 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.
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  33. ^ "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.
  34. ^ 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.
  35. ^ 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.
  36. ^ Michaelides M, et al. Fluorinated Mu-Opioid Receptor Agonists. WO 2024/196438
  37. ^ "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.
  38. ^ "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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