Isotonitazene

Last updated
Isotonitazene
Isotonitazene.svg
Clinical data
Routes of
administration 		By mouth, nasal spray, e-vape
Legal status
Legal status
Identifiers
  • N,N-diethyl-2-[2-[(4-isopropoxyphenyl)methyl]-5-nitro-benzimidazol-1-yl]ethanamine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C23H30N4O3
Molar mass 410.518 g·mol−1
3D model (JSmol)
  • CCN(CCn1c(Cc2ccc(cc2)OC(C)C)nc2c1ccc(c2)N(=O)=O)CC
  • 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

Isotonitazene is a benzimidazole-derived opioid analgesic drug related to etonitazene, [2] [3] [4] which has been sold as a designer drug. [5] [6] [7] It has only around half the potency of etonitazene in animal studies, [2] [8] [9] [10] [11] [12] [13] 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). [2] 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. [2] [14]

Contents

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. [15]

Isotonitazene has been detected in multiple fatalities in Europe since March 2019 [16] and in the U.S. since August 2019, as reported by NPS Discovery, the Center for Forensic Science Research and Education, and NMS Labs. [17] [18]

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, [19] which came into effect on 20 August 2020. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Benzimidazole</span> Chemical compound

Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals.

<span class="mw-page-title-main">Etonitazene</span> Chemical compound

Etonitazene, also known as EA-4941 or CS-4640, is a benzimidazole opioid, first reported in 1957, that has been shown to have approximately 1,000 to 1,500 times the potency of morphine in animals.

<span class="mw-page-title-main">Lofentanil</span> Opioid analgesic

Lofentanil or lofentanyl is one of the most potent opioid analgesics known and is an analogue of fentanyl, which was developed in 1960. It is most similar to the highly potent opioid carfentanil (4-carbomethoxyfentanyl), only slightly more potent. Lofentanil can be described as 3-methylcarfentanil, or 3-methyl-4-carbomethoxyfentanyl. While 3-methylfentanyl is considerably more potent than fentanyl itself, lofentanil is only slightly stronger than carfentanil. This suggests that substitution at both the 3 and 4 positions of the piperidine ring introduces steric hindrance which prevents μ-opioid affinity from increasing much further. As with other 3-substituted fentanyl derivatives such as ohmefentanyl, the stereoisomerism of lofentanil is very important, with some stereoisomers being much more potent than others.

<span class="mw-page-title-main">Metofoline</span> Chemical compound

Metofoline (INN), also known as methofoline (USAN), is an opioid analgesic drug discovered in the 1950s by a team of Swiss researchers at Hoffmann-La Roche.

<span class="mw-page-title-main">Clonitazene</span> Opioid analgesic

Clonitazene is an opioid analgesic of approximately three times the potency of morphine. It is related to etonitazene, an opioid of significantly higher potency. Clonitazene is not currently marketed. It is a controlled substance; in the United States it is a Schedule I Narcotic controlled substance with a DEA ACSCN of 9612 and an established manufacturing quota of 25 grams for 2022.

<span class="mw-page-title-main">Arylcyclohexylamine</span> Class of chemical compounds

Arylcyclohexylamines, also known as arylcyclohexamines or arylcyclohexanamines, are a chemical class of pharmaceutical, designer, and experimental drugs.

<span class="mw-page-title-main">BDPC</span> Synthetic opioid

BDPC is a potent fully synthetic opioid with a distinctive arylcyclohexylamine chemical structure. It was developed by Daniel Lednicer at Upjohn in the 1970s. Initial studies estimated that it was around 10,000 times the potency of morphine in animal models. However, later studies using more modern techniques assigned a value of 504 times the potency of morphine for the more active trans-isomer. This drug was first seized along with three kilograms of acetylfentanyl in an April 25, 2013 police action in Montreal, Canada, and has reportedly continued to be available on the designer drug market internationally. Analogues where the para-bromine is replaced by chlorine or a methyl group retain similar activity, while the meta-hydroxyl derivative demonstrated robust antagonist activity.

<span class="mw-page-title-main">Furanylfentanyl</span> Opioid analgesic

Furanylfentanyl (Fu-F) is an opioid analgesic that is an analog of fentanyl and has been sold as a designer drug. It has an ED50 value of 0.02 mg/kg in mice. This makes it approximately one fifth as potent as fentanyl.

<span class="mw-page-title-main">Thiafentanil</span> Chemical compound

Thiafentanil is a highly potent opioid analgesic that is an analog of fentanyl, and was invented in 1986. Its analgesic potency is slightly less than that of carfentanil, though with a faster onset of effects, shorter duration of action and a slightly lesser tendency to produce respiratory depression. It is used in veterinary medicine to anesthetise animals such as impala, usually in combination with other anesthetics such as ketamine, xylazine or medetomidine to reduce the prevalence of side effects such as muscle rigidity.

<span class="mw-page-title-main">Metonitazene</span> Chemical compound (analgesic drug)

Metonitazene is an analgesic compound related to etonitazene, which was first reported in 1957, and has been shown to have approximately 1000 times the potency of morphine by central routes of administration, but if used orally it has been shown to have approximately 10 times the potency of morphine.

<span class="mw-page-title-main">Etodesnitazene</span> Chemical compound

Etodesnitazene is a benzimidazole derived opioid analgesic drug, which was originally developed in the late 1950s alongside etonitazene and a range of related derivatives. It is many times less potent than etonitazene itself, but still 70x more potent than morphine in animal studies. Corresponding analogues where the N,N-diethyl group is replaced by piperidine or pyrrolidine rings also retain significant activity. Etodesnitazene has been sold as a designer drug, first being identified in both Poland and Finland in March 2020.

<span class="mw-page-title-main">Etonitazepipne</span> Benzimidazole derivative

Etonitazepipne is a benzimidazole derivative with opioid effects around 100 times more potent than morphine, which has been sold over the internet as a designer drug.

<span class="mw-page-title-main">Metodesnitazene</span> Chemical compound

Metodesnitazene is a benzimidazole derivative with opioid effects, though unlike related compounds such as metonitazene and etodesnitazene which are many times more potent, metodesnitazene is only around the same potency as morphine in animal studies. It was proposed by the DEA to be placed under legal control in the US in December 2021.

<span class="mw-page-title-main">Protonitazene</span> Chemical compound

Protonitazene is a benzimidazole derivative with potent opioid effects which has been sold over the internet as a designer drug since 2019, and has been identified in various European countries, as well as Canada, the US and Australia. It has been linked to numerous cases of drug overdose, and is a Schedule I drug in the US.

<span class="mw-page-title-main">Butonitazene</span> Chemical compound

Butonitazene is a benzimidazole derivative with opioid effects, which has been sold over the internet as a designer drug. It has relatively low potency compared to many related compounds, and has generally been encountered as a component of mixtures with other substances rather than in its pure form. However, it is still several times the potency of morphine and has been implicated in several cases of drug overdose. Butonitazene is a Schedule I drug in the US, along with several related compounds.

<i>N</i>-Desethylisotonitazene Chemical compound

N-Desethylisotonitazene (Norisotonitazene) is a benzimidazole derivative with potent opioid effects which has been sold as a designer drug. It was first identified as an active metabolite of the related compound isotonitazene, but was unexpectedly found to be similar potency compared to the parent compound, and is among the most potent opioid agonists in this family, around 20 times stronger than fentanyl. It has become an increasingly widespread drug of abuse in its own right, linked to numerous cases of drug overdose,and may be considered an analog of a schedule 1 drug in the US. On October 25 an intent to temporarily schedule Etonitazepipne and N-desethyl Isotonitazene was published. So on November 24 a month after publishing intent, it will most likely be placed in schedule 1.

<span class="mw-page-title-main">Protonitazepyne</span> Chemical compound

Protonitazepyne is a benzimidazole derivative with opioid effects, which has been sold as a designer drug over the internet, first being mentioned in mid 2022 and definitively identified in drug seizures in Canada in early 2023. It is an analogue of etonitazene where the ethoxy group has been extended to propoxy, and the N,N-diethyl substitution has been cyclised into a pyrrolidine ring. While formal studies into its pharmacology have yet to be carried out, it is believed to be slightly less potent than the ethoxy analogue etonitazepyne but still a potent opioid.

<span class="mw-page-title-main">Etoetonitazene</span> Chemical compound

Etoetonitazene is a benzimidazole derivative with opioid effects, first developed in the 1950s as part of the research that led to better-known compounds such as etonitazene. It is an analogue of etonitazene where the ethoxy sidechain has been extended to ethoxyethoxy. It is less potent than other benzimidazole class opioids, but is still a potent mu opioid receptor agonist with around 50x the potency of morphine, and has been sold as a designer drug since around 2022.

<span class="mw-page-title-main">Flunitazene</span> Designer drug with opioid effects

Flunitazene (Fluonitazene) is a benzimidazole derivative with opioid effects, first developed in the 1950s as part of the research that led to better-known compounds such as etonitazene. It is one of the least potent derivatives from this class to have appeared as a designer drug, with only around the same potency as morphine, but nevertheless has been sold since around 2020, and has been linked to numerous drug overdose cases.

References

  1. ↑ 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).
  2. 1 2 3 4 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ Power M (13 March 2020). "40 Americans Are Dying Every Month from Taking This New, Legal Opioid". Vice .
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ "Schedules of Controlled Substances: Temporary Placement of Isotonitazene in Schedule I". Federal Register. 18 June 2020.
  20. ↑ "Schedules of Controlled Substances: Temporary Placement of Isotonitazene in Schedule I". Federal Register. 20 August 2020.


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