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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, as well as West Africa. Some other benzimidazole-containing opioids are classified separately under the orphine subgroup. There is currently no medical usage due to the high potencies of certain analogs.[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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Relative analgesic activity values are derived from tests on mice and cannot be extrapolated directly to humans, though the same general activity trends apply. Relevant articles include:[5][6][7][8][9][10][11][12][13][14][15]

Like other synthetic opioids, benzimidazole opioids bind the mu-opioid receptor and may exhibit potency up to several hundred times that of morphine.[16][17][18][19][20]

See also

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References

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  1. ↑ 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.
  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.
  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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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. hdl:1854/LU-01J69XE5FSN27ZHJ074KWS7FG7. PMID 37658878.
  17. ↑ 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. PMC 11890208. PMID 38345920.
  18. ↑ 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.
  19. ↑ Kanamori T, Okada Y, Segawa H, Yamamuro T, Kuwayama K, Tsujikawa K, et al. (Apr 2023). "Analysis of highly potent synthetic opioid nitazene analogs and their positional isomers". Drug Test Anal. 15 (4): 449–457. doi:10.1002/dta.3415. PMID 36437623.
  20. ↑ Vandeputte MM, Glatfelter GC, Walther D, Layle NK, St Germaine DM, Ujváry I, et al. (2024). "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. 210 107503. doi:10.1016/j.phrs.2024.107503. PMC 11655282. PMID 39521025.
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