N-Ethylhexedrone

Source: Wikipedia, the free encyclopedia.
N-Ethylhexedrone
Legal status
Legal status
Pharmacokinetic data
MetabolismNeurometabolic
Identifiers
  • 2-(Ethylamino)-1-phenylhexan-1-one
CAS Number
PubChem CID
ChemSpider
UNII
JSmol)
  • CCCCC(NCC)C(=O)c1ccccc1
  • InChI=1S/C14H21NO/c1-3-5-11-13(15-4-2)14(16)12-9-7-6-8-10-12/h6-10,13,15H,3-5,11H2,1-2H3
  • Key:CWNKMHIETKEBCA-UHFFFAOYSA-N

N-Ethylhexedrone (also known as α-ethylaminocaprophenone, N-ethylnorhexedrone, hexen, and NEH) is a stimulant of the cathinone class[2][3] that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) with IC50 values of 0.0978 and 0.0467 μM, respectively.[4] N-Ethylhexedrone was first mentioned in a series of patents by Boehringer Ingelheim in the 1960s[5] which led to the development of the better-known drug methylenedioxypyrovalerone (MDPV).[6][failed verification] Since the mid-2010s, N-ethylhexedrone has been sold online as a designer drug.[7][8][9] In 2018, N-ethylhexedrone was the second most common drug of the cathinone class to be identified in Drug Enforcement Administration seizures.[10]

N-Ethylhexedrone was first synthesized by Boehringer Ingelheim in 1964.[11] It appears to have emerged on the online research chemical market in late 2015.[12] It is an example of a novel psychoactive substance specifically chosen to mimic the features of prohibited substances and bypass drug laws. It is one of a number of substances collectively referred to as "bath salts".[13]

User reports characterize N-ethylhexedrone as having euphoric stimulant effects comparable to those of

substituted cathinones, N-ethylhexedrone has gained notoriety for its association with compulsive redosing
and addictive behaviors when abused.

History and culture

N-Ethylhexedrone was patented by the German pharmaceutical company Boehringer Ingelheim in 1964 as a potential anorexigenic agent. The patent describes its synthesis together with other derivatives of aminoketone.[11]

The substance spread remarkably quickly in the NPS market in different European countries.

EMCDDA received notifications of the identification of this substance from other countries, such as Sweden, The Netherlands, France, Belgium and Slovenia.[14]

In 2017 it was the most frequent seized cathinone in the EU, Norway and Turkey.[15] In 2018, it was the most commonly identified cathinone after pentylone in Drug Enforcement Administration seizures.[13]

Chemistry

N-Ethylhexedrone is a derivative of

A-PHP), from which it differs by the substitution of a pyrrolidine group with an N-ethyl group.[11]

The compound is a molecule of the

amphetamines. Notably, the cathinone backbone can be modified in three different places to create hundreds of possible compounds, which include substituents on the aromatic ring (R2-R5), the alpha carbon (Rα), or the amine group (RN1, RN2).[16]

Relative to cathinone, N-ethylhexedrone consists of two added substitutions. At the Rα position, a n-butyl substitution forms a hexan chain. The second substitution is an ethyl group, that's attached to the amine group at RN2, thus forming N-ethyl.

Pharmacology

Hexen

Very little data exists on the human pharmacokinetics and pharmacodynamics of N-ethylhexedrone and many other recently introduced substituted cathinones, aside from post-mortem results in overdose cases.

neurotransmitters from the synapse. Furthermore, they may cause release of biogenic amines from intracellular stores.[21] It appears that N-ethylhexedrone has high preference for the dopamine transporter.[11]

Based on the structure and assuming that N-ethylhexedrone is metabolized similarly to other cathinones, this compound is likely metabolized through N-dealkylation and/or reduction of the carbonyl group followed by N-dealkylation.[11]

Synthetic cathinones are generally less able than amphetamines to cross the blood–brain barrier because the beta-keto group causes an increase in polarity. Unlike other synthetic cathinones, pyrrolidine derivatives have a higher ability to cross the blood–brain barrier because the pyrrolidine ring confers a low polarity to these molecules. The studies on the metabolism of synthetic cathinones have shown that they are N-demethylated, the keto group is reduced to hydroxyl and ring alkyl groups are oxidised.[22]

Legal status

Internationally, N-ethylhexedrone was added to the UN Convention on Psychotropic Substances as a Schedule II controlled substance in March 2020.[23][24]

  • Brazil: Possession, production and sale is illegal as it is listed on Portaria SVS/MS nº 344 since June 5, 2017.[25]
  • Canada: N-Ethylhexedrone is a Schedule I controlled substance.[11]
  • Germany: N-Ethylhexedrone is controlled under the NpSG[26] (New Psychoactive Substances Act) as of November 26, 2016.[27] Production and import with the aim to place it on the market, administration to another person, placing it on the market and trading is punishable. Possession is illegal but not punishable.[28][29] The legislator considers it possible that orders of N-ethylhexedrone are punishable as an incitement to place it on the market.[30]
  • Hungary: N-Ethylhexedrone is controlled as a new psychoactive substance.[11]
  • Ireland: N-Ethylhexedrone is controlled under SI 173/2017 under Schedule 1, paragraph 1(b) (page 35) as the substance is structurally derived from 2-amino-1-phenyl-1-propanone and is I the 3-position of the propanone side-chain with an alkyl substituent in this case, an ethyl group (subparagraph iii).[31]
  • Japan: N-Ethylhexedrone is a controlled substance.[32]
  • Sweden: N-Ethylhexedrone was classified as a potentially dangerous substance in Sweden on June 21, 2016, and is thus a controlled substance but neither narcotics-classified or fully outlawed.[33]
  • Switzerland: N-Ethylhexedrone can be considered a controlled substance as a defined derivative of Cathinone under Verzeichnis E point 1. It is legal when used for scientific or industrial use.[34]
  • United Kingdom: N-Ethylhexedrone is a Class B drug in the United Kingdom as a result of the cathinone catch-all clause.[35]
  • United States: N-Ethylhexedrone was placed in Schedule I by a DEA temporary scheduling order effective July 2019[36] and was permanently placed in Schedule I effective June 2022.[37]

See also

References

  1. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. doi:10.3408/jafst.19.77
    .
  3. hdl:20.500.12128/9638
    .
  4. PMID 30397775
    .
  5. ^ DE 1545591, Herbert K, Karl Z, Gerhard L, "Verfahren zur Herstellung von α-Aminoketonen mit heterocyclischer Aminogruppe", published 28 May 1965, assigned to Boehringer Ingelheim 
  6. PMID 24116392
    .
  7. ^ "2-(Ethylamino)-1-phenylhexan-1-one". New Synthetic Drugs Database. Archived from the original on 2017-05-20. Retrieved 2016-08-28.
  8. ^ "Analytical Report - N-Ethylhexedrone" (PDF). European Project RESPONSE.
  9. PMID 27863142
    .
  10. ^ "Emerging Threat Report: Annual 2018" (PDF). Special Testing and Research Laboratory, Drug Enforcement Administration.
  11. ^ a b c d e f g h Critical Review Report: N-Ethylhexedrone (PDF). Expert Committee on Drug Dependence (ECDD). Vol. Forty-second Meeting. World Health Organisation (WHO). October 2019.
  12. ^ "N-Ethylhexedrone". Google Trends. Retrieved October 16, 2020.
  13. ^
    PMID 30397775
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  14. PMID 29792142
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  15. ISBN 978-92-9497-459-4
    .
  16. PMID 27863142
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  17. S2CID 221496238
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  18. PMID 33048166
    .
  19. PMID 34849994
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  20. S2CID 226271372
    .
  21. PMID 10528135
    .
  22. PMID 20540700
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  23. ^ "WHO: World Health Organization recommends 12 NPS for scheduling". December 2019. Retrieved October 16, 2020.
  24. ^ "CND accepts all WHO recommendations on the control of several psychoactive substances from the 42nd ECDD meeting". World Health Organization (WHO). March 18, 2020. Retrieved October 16, 2020.
  25. ISSN 1677-7042. N°106. Archived from the original
    on January 16, 2020.
  26. ^ "Anlage NpSG" (in German). Bundesamt für Justiz [Federal Office of Justice]. Retrieved December 10, 2019.
  27. OCLC 1004462279
    .
  28. ^ "§ 4 NpSG" (in German). Bundesamt für Justiz [Federal Office of Justice]. Retrieved December 10, 2019.
  29. ^ "§ 3 NpSG" (in German). Bundesamt für Justiz [Federal Office of Justice]. Retrieved December 10, 2019.
  30. ^ "Gesetzentwurf der Bundesregierung: Entwurf eines Gesetzes zur Bekämpfung der Verbreitung neuer psychoaktiver Stoffe" (PDF) (in German). Deutscher Bundestag. May 30, 2016. p. 20. Drucksache 18/8579.
  31. ^ "Information Note-COM (2019) 631 Final" (PDF). Controlled Drugs and Pharmacy Legislation Unit. January 13, 2020.
  32. ^ "指定薬物一覧" (PDF) (in Japanese). 厚生労働省 [Ministry of Health, Labour and Welfare (MHLW)]. Retrieved December 27, 2019.
  33. ^ "31 nya ämnen kan klassas som narkotika eller hälsofarlig vara" (in Swedish). Folkhälsomyndigheten [Public Health Agency of Sweden]. June 21, 2016. Retrieved October 17, 2020.
  34. ^ "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020.
  35. ^ "Part II: Class B Drugs". Misuse of Drugs Act 1971. UK Government. Retrieved October 18, 2020.
  36. ^ "Temporary Placement of N-Ethylhexedrone, α-PHP, 4–MEAP, MPHP, PV8, and 4-Chloro-α-PVP in Schedule I". Federal Register. Vol. 84, no. 138. Drug Enforcement Administration (DEA). July 18, 2019. pp. 34291–34297. Retrieved October 18, 2020.
  37. ^ "Schedules of Controlled Substances: Placement of N-Ethylhexedrone, alpha-Pyrrolidinohexanophenone, 4-Methyl-alpha-ethylaminopentiophenone, 4′-Methyl-alpha-pyrrolidinohexiophenone, alpha-Pyrrolidinoheptaphenone, and 4′-Chloro-alpha-pyrrolidinovalerophenone in Schedule I" (PDF). Federal Register. Vol. 87, no. 105. Drug Enforcement Administration (DEA). June 1, 2022. pp. 32996–32999.
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