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N-Ethylhexedrone

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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
Legal status
Legal status
Pharmacokinetic data
MetabolismNeurometabolic
Identifiers
  • 2-(Ethylamino)-1-phenylhexan-1-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC14H21NO
Molar mass219.328 g·mol−1
3D model (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 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 crack-cocaine and α-PVP-type compounds, particularly when they are insufflated or vaporized. Like other substituted cathinones, N-ethylhexedrone has gained notoriety for its association with compulsive redosing and addictive behaviors when abused.

History and culture

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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.[11] It was first identified in a sample from the Belgian Customs laboratory which was received at the JRC in November 2015. In January 2016, it was identified at the JRC in a sample provided by French Customs. Subsequently, in February 2016, the 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

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N-Ethylhexedrone is a derivative of hexedrone, in which the methyl group attached to the nitrogen atom is substituted by an ethyl group. It is structurally similar to pentedrone, and also α-pyrrolidinohexiophenone (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 cathinone chemical class. The term "substituted cathinone" refers to a broad array of substances based on cathinone, the principally active constituent of the khat plant. Cathinone is principally constituted of a amphetamine core (a phenethylamine core with an alkyl group attached to the alpha carbon) and an oxygen group attached to the beta carbon. Cathinones are also known as the beta-ketone (βk) (double-bonded oxygen to the β-carbon) analogs of 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

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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.[17][18][19] Like amphetamines, synthetic cathinones exert their stimulating and sympathomimetic effects via increasing synaptic concentration of catecholamines such as dopamine, serotonin and norepinephrine.[20] These molecules are able to inhibit monoamine reuptake transporters producing a decreased clearance of the 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]

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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

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References

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  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. ^ Matsuta S, Katagi M, Nishioka H, Kamata H, Sasaki K, Shima N, et al. (2014). "Structural characterization of cathinone-type designer drugs by EI mass spectrometry". Japanese Journal of Forensic Science and Technology (in Japanese). 19 (2): 77–89. doi:10.3408/jafst.19.77.
  3. ^ Kuś P, Rojkiewicz M, Kusz J, Książek M, Sochanik A (July 2019). "Spectroscopic characterization and crystal structures of four hydrochloride cathinones: N-ethyl-2-amino-1-phenylhexan-1-one (hexen, NEH), N-methyl-2-amino-1-(4-methylphenyl)-3-methoxypropan-1-one (mexedrone), N-ethyl-2-amino-1-(3,4-methylenedioxyphenyl)pentan-1-one (ephylone) and N-butyl-2-amino-1-(4-chlorophenyl)propan-1-one (4-chlorobutylcathinone)". Forensic Toxicology. 37 (2): 456–464. doi:10.1007/s11419-019-00477-y. hdl:20.500.12128/9638.
  4. ^ Eshleman AJ, Nagarajan S, Wolfrum KM, Reed JF, Swanson TL, Nilsen A, Janowsky A (March 2019). "Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters". Psychopharmacology. 236 (3): 939–952. doi:10.1007/s00213-018-5059-5. PMC 6500773. 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. ^ Kolanos R, Solis E, Sakloth F, De Felice LJ, Glennon RA (December 2013). ""Deconstruction" of the abused synthetic cathinone methylenedioxypyrovalerone (MDPV) and an examination of effects at the human dopamine transporter". ACS Chemical Neuroscience. 4 (12): 1524–1529. doi:10.1021/cn4001236. PMC 3867964. PMID 24116392.
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  8. ^ "Analytical Report - N-Ethylhexedrone" (PDF). European Project RESPONSE.
  9. ^ Liu C, Jia W, Li T, Hua Z, Qian Z (August 2017). "Identification and analytical characterization of nine synthetic cathinone derivatives N-ethylhexedrone, 4-Cl-pentedrone, 4-Cl-α-EAPP, propylone, N-ethylnorpentylone, 6-MeO-bk-MDMA, α-PiHP, 4-Cl-α-PHP, and 4-F-α-PHP". Drug Testing and Analysis. 9 (8): 1162–1171. doi:10.1002/dta.2136. PMID 27863142.
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  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. ^ a b Eshleman AJ, Nagarajan S, Wolfrum KM, Reed JF, Swanson TL, Nilsen A, Janowsky A (March 2019). "Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters". Psychopharmacology. 236 (3): 939–952. doi:10.1007/s00213-018-5059-5. eISSN 1432-2072. OCLC 2409222. PMC 6500773. PMID 30397775.
  14. ^ Guillou C, Reniero F, Lobo Vicente J, Holland M, Kolar K, Chassaigne H, et al. (2018). "Collaboration of the Joint Research Centre and European Customs Laboratories for the Identification of New Psychoactive Substances". Current Pharmaceutical Biotechnology. 19 (2): 91–98. doi:10.2174/1389201019666180523122717. OCLC 1085815223. PMC 6110040. PMID 29792142.
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  16. ^ Liu C, Jia W, Li T, Hua Z, Qian Z (August 2017). "Identification and analytical characterization of nine synthetic cathinone derivatives N-ethylhexedrone, 4-Cl-pentedrone, 4-Cl-α-EAPP, propylone, N-ethylnorpentylone, 6-MeO-bk-MDMA, α-PiHP, 4-Cl-α-PHP, and 4-F-α-PHP". Drug Testing and Analysis. 9 (8): 1162–1171. doi:10.1002/dta.2136. eISSN 1942-7611. OCLC 231680670. PMID 27863142.
  17. ^ La Maida N, Di Trana A, Giorgetti R, Tagliabracci A, Busardò FP, Huestis MA (February 2021). "A Review of Synthetic Cathinone-Related Fatalities From 2017 to 2020". Therapeutic Drug Monitoring. 43 (1): 52–68. doi:10.1097/FTD.0000000000000808. PMID 32881779. S2CID 221496238.
  18. ^ Domagalska E, Banaszkiewicz L, Woźniak MK, Kata M, Szpiech B, Kaliszan M (July 2021). "Fatal N-Ethylhexedrone Intoxication". Journal of Analytical Toxicology. 45 (6): e1–e6. doi:10.1093/jat/bkaa159. PMC 8272529. PMID 33048166.
  19. ^ Pieprzyca E, Skowronek R, Czekaj P (January 2023). "Toxicological Analysis of Cases of Mixed Poisonings with Synthetic Cathinones and Other Drugs of Abuse". Journal of Analytical Toxicology. 46 (9): 1008–1015. doi:10.1093/jat/bkab119. PMID 34849994.
  20. ^ Gatch MB, Shetty RA, Sumien N, Forster MJ (July 2021). "Behavioral effects of four novel synthetic cathinone analogs in rodents". Addiction Biology. 26 (4): e12987. doi:10.1111/adb.12987. PMID 33155384. S2CID 226271372.
  21. ^ Cozzi NV, Sievert MK, Shulgin AT, Jacob P, Ruoho AE (September 1999). "Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines". European Journal of Pharmacology. 381 (1): 63–69. doi:10.1016/s0014-2999(99)00538-5. eISSN 1879-0712. OCLC 01568459. PMID 10528135.
  22. ^ Meyer MR, Maurer HH (June 2010). "Metabolism of designer drugs of abuse: an updated review". Current Drug Metabolism. 11 (5): 468–482. doi:10.2174/138920010791526042. eISSN 1875-5453. OCLC 55201006. PMID 20540700.
  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. ^ "RESOLUÇÃO-RDC No- 159, DE 2 DE JUNHO DE 2017". Diário Official da União (in Portuguese). Governo Federal do Brasil [Federal Government of Brazil] (published June 5, 2017). May 23, 2017. p. 103. 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. ^ "Gesetz zur Bekämpfung der Verbreitung neuer psychoaktiver Stoffe" (PDF). Bundesgesetzblatt Jahrgang 2016 Teil I Nr. 55 (in German). Bundesanzeiger Verlag (published November 25, 2016). November 21, 2016. pp. 2615–2622. ISSN 0341-1095. 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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