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List of benzimidazole opioids

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Benzimidazole core structure

Benzimidazole opioids are a class of synthetic opioids that contain a benzimidazole core structure. The pain-relieving properties of these substances were discovered in the mid-1950s by the Swiss company Ciba AG. The most important subgroup are the nitazene opioids, which since 2019 have become increasingly widespread as narcotics in North America and Europe. Due to unacceptable side effects like respiratory depression, there is no medical use for benzimidazole opioids.[1]

History

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Desnitazene

In 1957, the pharmaceutical research department of Ciba AG published the discovery of the (low) analgesic effect of 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene).[2] Shortly afterwards, the nitazenes were discovered in structure-activity relationship studies.[3][4]

Structure-activity relationship

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The class of substances is defined chemically by the presence of the benzimidazole core structure and pharmacologically by opioid activity. The compounds are derived from the historical prototype 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene). The replacement of the N,N-dialkylamino unit by pyrrolidinyl or piperidinyl, which is found in nitazepyne and nitazepipne compounds, falls into the spectrum of designer drugs. Substitution of the benzyl for thienylmethyl, pyridylmethyl, α-napthylmethyl or styryl has a potency-reducing effect.[5][6] Substitution in position 4 of the benzyl affects analgesic potency in the following order: ethoxy > isopropyloxy > n-propyloxy > methoxy > methylthio > H/Cl/F > hydroxy. The most potent of the known compounds contain a nitro group in position 5.[6] The replacement of benzimidazole with an indole has been known from studies conducted by Ciba AG since 1963.[7]

Relative analgesic activity values are derived from tests on mice and cannot be extrapolated directly to humans, though the same general activity trends apply.[8][9][10][11][12][13][14][15][16][17][18][excessive citations]

Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine.[19][20][21][22][23]

Prevalence

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In the early 2020s, the substances have been recognized as emerging drugs of abuse.[24][25] Isotonitazene was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States in March and April 2019.[26] 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.[25] Nitazenes have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom[27] and New Zealand.[28]

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. Most cases of abuse and overdose are linked to potent derivatives such as metonitazene, protonitazene, isotonitazene, etonitazepyne, and etodesnitazene.

Table of benzimidazole opioids

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Structure Name Ring sub. Analgesic potency (morphine = 1) PubChem CAS #
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 194537-85-4
meta-Metonitazene 3-methoxy 2 96168-49-9
Metonitazene 4-methoxy 100 53316366 14680-51-4
Metonitazepyne 4-methoxy 3053113-16-6
Metonitazepipne 4-methoxy
N-Desethylmetonitazene 4-methoxy
Metomethazene 4-methoxy 95138-58-2
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 75821-80-6
Etomethazene 4-ethoxy 20 168310446 95293-25-7
Etonitazene 5-trifluoromethyl analogue (Etotriflazene)[30] 4-ethoxy 21815908 15451-92-0
5-Trifluoromethyl isotodesnitazene 4-isopropoxy 15451-92-0
Etonitazene 5-cyano analogue (Etocyanazene) [31] 4-ethoxy 27268 15419-87-1
Etonitazene 5-acetyl analogue (Etoacetazene) [32] 4-ethoxy 25957 13406-60-5
Etonitazene 5,6-dichloro analogue (Etodicloazene) 4-ethoxy 102476-04-0
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 [33] 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) [34] 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 [35] 4-(2-fluoroethoxy) 172332078
Trifluorometonitazene 4-trifluoromethoxy 954386-78-8
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 101795-25-9
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[36] 3,4-methylenedioxy
Ethyleneoxynitazene[37] fused tetrahydrofuran

See also

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References

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  2. ^ Hunger A, Kebrle J, Rossi A, Hoffmann K (1957). "Synthesis of basic substituted, analgesically active benzimidazole derivatives". Experientia. 13 (10): 400–1. doi:10.1007/BF02161116. PMID 13473817.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ US patent 2935514, Hoffman K, Hunger A, "BENZMDAZOLES (sic)", published 1960-05-03, assigned to Ciba Pharmaceutical Products Inc. 
  4. ^ Drug Enforcement Administration (June 2021). "Benzimidazole Opioids" (PDF). Retrieved 6 January 2022.
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  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. ^ 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.
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  21. ^ 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.
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  33. ^ 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.
  34. ^ 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.
  35. ^ Michaelides M, et al. Fluorinated Mu-Opioid Receptor Agonists. WO 2024/196438
  36. ^ "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.
  37. ^ "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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