List of benzimidazole opioids

A number of benzimidazole opioids have been developed, with the best known being the highly potent but never marketed etonitazene. The structure-activity relationship 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.[1][2][3][4][5][6][7][8][9][10][11][12][13]

A 2019 publication[14] has shown the possibility the previously assumed binding position of the benzimidazole class,[15] 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 very only a small area in common with the fentanyl class.

Table of benzimidazole opioids

Chemical structure Drug name Ring substitution Analgesic potency (morphine = 1) PubChem CAS number
1-diethylaminoethyl-2-benzyl-benzimidazole hydrogen 0.1 28787
Metodesnitazene (Metazene) 4-methoxy 1 26412 14030-77-4
1071546-40-1 (HCl)
Etodesnitazene (Etazene) 4-ethoxy 70 149797386
Etodesnitazene pyrrolidine analogue 4-ethoxy 20
Etodesnitazene piperidine analogue 4-ethoxy 10
Protodesnitazene 4-(n-propoxy) 10
Isotodesnitazene 4-isopropoxy ~75
Nitazene hydrogen 2 15327524
meta-Metonitazene 3-methoxy 2
Metonitazene 4-methoxy 100 53316366 14680-51-4
Dimetonitazene 3,4-dimethoxy 10
α-methyl-metonitazene 4-methoxy 50
Metonitazene phenethyl homologue 4-methoxy 50
Etonitazene 4-ethoxy 1000 13493 911-65-9
O-Desmethyl-etonitazene 4-hydroxy 1 94758-81-3
Etonitazene 5-amino metabolite 4-ethoxy 2 13408927
Etonitazene N,N-dimethyl analogue 4-ethoxy 20
Etonitazepyne 4-ethoxy
Etonitazene piperidine analogue 4-ethoxy 100
Etonitazene morpholine analogue 4-ethoxy 2
Etonitazene 6-nitro isomer 4-ethoxy 20
Protonitazene 4-(n-propoxy) 200 119276-01-6
Isotonitazene 4-isopropoxy 500 145721979 14188-81-9
N-desethyl-isotonitazene 4-isopropoxy ~1000
Butonitazene 4-butoxy 5 95810-54-1
Etoetonitazene 4-ethoxyethoxy 50
Fluonitazene 4-fluoro 1 2728-91-8
Clonitazene 4-chloro 3 62528 3861-76-5
α-carboxamido-clonitazene 4-chloro 3
Bronitazene 4-bromo 5
Methylnitazene 4-methyl 10
Ethylnitazene 4-ethyl 20
Propylnitazene 4-propyl 50
t-Butylnitazene 4-(tert-butyl) 2
Acetoxynitazene 4-acetoxy 5
Methylthionitazene 4-methylthio 50
Ethylthionitazene 4-ethylthio 30
Etodesnitazene phenylthiol analogue 4-ethoxy 1 21045
Etodesnitazene phenylthiol / pyrrolidine analogue 4-ethoxy 2 19846499

See also

References
  1. US 2944062, Hoffman K, Hunger A, "Certain Alpha (1-diethylaminoethyl (2), Alpha Aryl Acetamides", issued 5 July 1960, assigned to Ciba Pharma Products Inc.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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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