Isotonitazene

Isotonitazene is a benzimidazole-derived opioid analgesic drug related to etonitazene,^[3][4][5] which has been sold as a designer drug.^[6][7][8] It has only around half the potency of etonitazene in animal studies,^{[3][9][10][11][12][13][14]} but it is likely even less potent in humans as was seen with etonitazene (1000 times as potent as morphine in animal models yet only 60 times as potent in humans).^[3] Isotonitazene (obtained from an online vendor) was fully characterized in November 2019 in a paper where the authors performed a full analytical structure elucidation in addition to determination of the potency at the μ-opioid receptor using a biological functional assay in vitro. While isotonitazene was not compared directly to morphine in this assay, it was found to be around 2.5 times more potent than hydromorphone and slightly more potent than fentanyl.^[3][15]

Isotonitazene

Clinical data
Routes of administration	By mouth, nasal spray, e-vape
Legal status
Legal status	BR: Class F1 (Prohibited narcotics) DE: Anlage II (Authorized trade only, not prescriptible) UK: Under Psychoactive Substances Act US: Schedule I Illegal in Belgium, Finland[1] and Sweden[2]
Identifiers
IUPAC name N,N-diethyl-2-[2-[(4-isopropoxyphenyl)methyl]-5-nitro-benzimidazol-1-yl]ethanamine
CAS Number	14188-81-9
PubChem CID	145721979
ChemSpider	73962294
UNII	ZFY1ZBQ8AV
KEGG	C22725
CompTox Dashboard (EPA)	DTXSID201126188
Chemical and physical data
Formula	C23H30N4O3
Molar mass	410.518 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCN(CCn1c(Cc2ccc(cc2)OC(C)C)nc2c1ccc(c2)N(=O)=O)CC
InChI InChI=1S/C23H30N4O3/c1-5-25(6-2)13-14-26-22-12-9-19(27(28)29)16-21(22)24-23(26)15-18-7-10-20(11-8-18)30-17(3)4/h7-12,16-17H,5-6,13-15H2,1-4H3 Key:OIOQREYBGDAYGT-UHFFFAOYSA-N

Side effects

Side effects of benzimidazole derived opioids are likely to be similar to those of fentanyl, which include itching, nausea and potentially serious respiratory depression, which can be life-threatening.^[16]

Isotonitazene has been detected in multiple fatalities in Europe since March 2019^[17] and in the U.S. since August 2019, as reported by NPS Discovery, the Center for Forensic Science Research and Education, and NMS Labs.^[18][19]

Legal status

The US Drug Enforcement Administration issued a notice of intent to publish a temporary order to schedule isotonitazene in Schedule I of the Controlled Substances Act,^[20] which came into effect on 20 August 2020.^[21]

See also

• BIM-018
• Clonitazene
• Etonitazene
• Etonitazepyne
• Etazen
• Metonitazene
• Protonitazene
• Secbutonitazene

References

1. https://finlex.fi/fi/laki/ajantasa/2008/20080543 ^{[bare URL]}
2. Riksdagsförvaltningen. "Förordning (1992:1554) om kontroll av narkotika Svensk författningssamling 1992:1992:1554 t.o.m. SFS 2021:301 - Riksdagen". www.riksdagen.se (in Swedish).
3. Blanckaert P, Cannaert A, Van Uytfanghe K, Hulpia F, Deconinck E, Van Calenbergh S, Stove C (April 2020). "Report on a novel emerging class of highly potent benzimidazole NPS opioids: Chemical and in vitro functional characterization of isotonitazene". Drug Testing and Analysis. 12 (4): 422–430. doi:10.1002/dta.2738. PMID 31743619. S2CID 208187034.
4. Casy AF, Wright J (October 1966). "Ionisation constants and partition coefficients of some analgesically active 2-benzylbenzimidazole derivatives and related compounds". The Journal of Pharmacy and Pharmacology. 18 (10): 677–683. doi:10.1111/j.2042-7158.1966.tb07782.x. PMID 4382076. S2CID 41516830.
5. Ujváry I, Christie R, Evans-Brown M, Gallegos A, Jorge R, de Morais J, Sedefov R (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.
6. Power M (13 March 2020). "40 Americans Are Dying Every Month from Taking This New, Legal Opioid". Vice.
7. Zagorski CM, Myslinski JM, Hill LG (September 2020). "Isotonitazene as a contaminant of concern in the illegal opioid supply: A practical synthesis and cost perspective". The International Journal on Drug Policy. 86: 102939. doi:10.1016/j.drugpo.2020.102939. PMID 32977186. S2CID 221939376.
8. Critical Review Report: Isotonitazene (PDF). Expert Committee on Drug Dependence, Forty-third Meeting. Geneva: World Health Organization. 12–20 October 2020. p. 7. Retrieved 20 May 2022. Street names: Iso; Nitazene; Toni.
9. 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): 400–401. doi:10.1007/BF02161116. PMID 13473817. S2CID 32179439.
10. 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.
11. 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.
12. Rossi A, Hunger A, Kebrle J, 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.
13. Rossi A, Hunger A, Kebrle J, 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.
14. Gross F, Turrian H (October 1957). "[Benzimidazole derivatives with strong analgesic effects]" [Benzimidazole derivatives with strong analgesic effects]. Experientia. 13 (10): 401–403. doi:10.1007/BF02161117. PMID 13473818. S2CID 6824038.
15. Vandeputte MM, Cannaert A, Stove CP (November 2020). "In vitro functional characterization of a panel of non-fentanyl opioid new psychoactive substances". Archives of Toxicology. 94 (11): 3819–3830. doi:10.1007/s00204-020-02855-7. hdl:1854/LU-8687070. PMID 32734307. S2CID 220881657.
16. Malcolm N, Palkovic B, Sprague D, Calkins M, Lanham J, Halberstadt A, Stucke A, McCorvy J (July 2023). "Mu-opioid receptor selective superagonists produce prolonged respiratory depression". iScience. 26 (7): 107121. doi:10.1016/j.isci.2023.107121. PMC 10320493. PMID 37416459.
17. 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.
18. Krotulski AJ, Papsun DM, Kacinko SL, Logan BK (July 2020). "Isotonitazene Quantitation and Metabolite Discovery in Authentic Forensic Casework". Journal of Analytical Toxicology. 44 (6): 521–530. doi:10.1093/jat/bkaa016. PMID 32091095.
19. Shover CL, Falasinnu TO, Freedman RB, Humphreys K (November 2020). "Emerging Characteristics of Isotonitazene-Involved Overdose Deaths: A Case-Control Study". Journal of Addiction Medicine. 15 (5): 429–431. doi:10.1097/ADM.0000000000000775. PMC 8141068. PMID 33234804.
20. "Schedules of Controlled Substances: Temporary Placement of Isotonitazene in Schedule I". Federal Register. 18 June 2020.
21. "Schedules of Controlled Substances: Temporary Placement of Isotonitazene in Schedule I". Federal Register. 20 August 2020.