N-Ethylhexedrone Explained

N-Ethylhexedrone (also known as α-ethylaminocaprophenone, N-ethylnorhexedrone, hexen, and NEH) is a stimulant of the cathinone class[1] [2] that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) with IC50 values of 0.0978 and 0.0467 μM, respectively.[3] N-Ethylhexedrone was first mentioned in a series of patents by Boehringer Ingelheim in the 1960s[4] which led to the development of the better-known drug methylenedioxypyrovalerone (MDPV).[5] Since the mid-2010s, N-ethylhexedrone has been sold online as a designer drug.[6] [7] [8] In 2018, N-ethylhexedrone was the second most common drug of the cathinone class to be identified in Drug Enforcement Administration seizures.[9]

N-Ethylhexedrone was first synthesized by Boehringer Ingelheim in 1964.[10] It appears to have emerged on the online research chemical market in late 2015.[11] 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".[12]

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

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.

The substance spread remarkably quickly in the NPS market in different European countries. 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.[13]

In 2017 it was the most frequent seized cathinone in the EU, Norway and Turkey.[14] In 2018, it was the most commonly identified cathinone after pentylone in Drug Enforcement Administration seizures.

Chemistry

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.

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).[15]

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

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.[16] [17] [18] Like amphetamines, synthetic cathinones exert their stimulating and sympathomimetic effects via increasing synaptic concentration of catecholamines such as dopamine, serotonin and norepinephrine.[19] 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.[20] It appears that N-ethylhexedrone has high preference for the dopamine transporter.

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.

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.[21]

Legal status

Internationally, N-ethylhexedrone was added to the UN Convention on Psychotropic Substances as a Schedule II controlled substance in March 2020.[22] [23]

See also

Notes and References

  1. Matsuta S, Katagi M, Nishioka H, Kamata H, Sasaki K, Shima N, Kamata T, Miki A, Tatsuno M, Zaitsu K, Tsuboi K . 6 . Structural characterization of cathinone-type designer drugs by EI mass spectrometry . Japanese Journal of Forensic Science and Technology . 2014 . 77–89 . 19 . 2 . 10.3408/jafst.19.77 . ja. free .
  2. Kuś P, Rojkiewicz M, Kusz J, Książek M, Sochanik A . 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 . July 2019 . 456–464 . 37 . 2 . 10.1007/s11419-019-00477-y . free . 20.500.12128/9638 . free .
  3. Eshleman AJ, Nagarajan S, Wolfrum KM, Reed JF, Swanson TL, Nilsen A, Janowsky A . Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters . Psychopharmacology . 236 . 3 . 939–952 . March 2019 . 30397775 . 6500773 . 10.1007/s00213-018-5059-5 .
  4. Herbert K, Karl Z, Gerhard L . Boehringer Ingelheim . DE . 1545591 . Verfahren zur Herstellung von α-Aminoketonen mit heterocyclischer Aminogruppe . 28 May 1965.
  5. Kolanos R, Solis E, Sakloth F, De Felice LJ, Glennon RA . "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 . December 2013 . 24116392 . 3867964 . 10.1021/cn4001236 .
  6. Web site: 2-(Ethylamino)-1-phenylhexan-1-one . New Synthetic Drugs Database . 2016-08-28 . https://web.archive.org/web/20170520171640/http://nsddb.eu/substance/615/ . 2017-05-20 . dead .
  7. Web site: Analytical Report - N-Ethylhexedrone . European Project RESPONSE.
  8. Liu C, Jia W, Li T, Hua Z, Qian Z . 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 . August 2017 . 27863142 . 10.1002/dta.2136 .
  9. Web site: Emerging Threat Report: Annual 2018 . Special Testing and Research Laboratory, Drug Enforcement Administration .
  10. Critical Review Report: N-Ethylhexedrone. Forty-second Meeting. October 2019. Expert Committee on Drug Dependence (ECDD). World Health Organisation (WHO).
  11. Web site: N-Ethylhexedrone. Google Trends. October 16, 2020.
  12. Eshleman AJ, Nagarajan S, Wolfrum KM, Reed JF, Swanson TL, Nilsen A, Janowsky A . Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters . Psychopharmacology . 236 . 3 . 939–952 . March 2019 . 30397775 . 6500773 . 10.1007/s00213-018-5059-5 . 2409222 . 1432-2072 .
  13. Guillou C, Reniero F, Lobo Vicente J, Holland M, Kolar K, Chassaigne H, Tirendi S, Schepers H . 6 . Collaboration of the Joint Research Centre and European Customs Laboratories for the Identification of New Psychoactive Substances . Current Pharmaceutical Biotechnology . 19 . 2 . 91–98 . 2018 . 29792142 . 6110040 . 10.2174/1389201019666180523122717 . 1085815223 .
  14. Book: EU Drug Markets Report 2019. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA); Europol. 10.2810/796253. 978-92-9497-459-4. 2019. 185. free. European Monitoring Centre for Drugs Drug Addiction. European Union Agency for Law Enforcement Cooperation.
  15. Liu C, Jia W, Li T, Hua Z, Qian Z . 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 . August 2017 . 27863142 . 10.1002/dta.2136 . 231680670 . 1942-7611 .
  16. La Maida N, Di Trana A, Giorgetti R, Tagliabracci A, Busardò FP, Huestis MA . A Review of Synthetic Cathinone-Related Fatalities From 2017 to 2020 . Therapeutic Drug Monitoring . 43 . 1 . 52–68 . February 2021 . 32881779 . 10.1097/FTD.0000000000000808 . 221496238 .
  17. Domagalska E, Banaszkiewicz L, Woźniak MK, Kata M, Szpiech B, Kaliszan M . Fatal N-Ethylhexedrone Intoxication . Journal of Analytical Toxicology . 45 . 6 . e1–e6 . July 2021 . 33048166 . 8272529 . 10.1093/jat/bkaa159 .
  18. Pieprzyca E, Skowronek R, Czekaj P . Toxicological Analysis of Cases of Mixed Poisonings with Synthetic Cathinones and Other Drugs of Abuse . Journal of Analytical Toxicology . 46 . 9 . 1008–1015 . January 2023 . 34849994 . 10.1093/jat/bkab119 .
  19. Gatch MB, Shetty RA, Sumien N, Forster MJ . Behavioral effects of four novel synthetic cathinone analogs in rodents . Addiction Biology . 26 . 4 . e12987 . July 2021 . 33155384 . 10.1111/adb.12987 . 226271372 .
  20. Cozzi NV, Sievert MK, Shulgin AT, Jacob P, Ruoho AE . Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines . European Journal of Pharmacology . 381 . 1 . 63–69 . September 1999 . 10528135 . 10.1016/s0014-2999(99)00538-5 . Alexander Shulgin . 01568459 . 1879-0712 .
  21. Meyer MR, Maurer HH . Metabolism of designer drugs of abuse: an updated review . Current Drug Metabolism . 11 . 5 . 468–482 . June 2010 . 20540700 . 10.2174/138920010791526042 . 55201006 . 1875-5453 .
  22. Web site: WHO: World Health Organization recommends 12 NPS for scheduling. December 2019. October 16, 2020.
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  24. Web site: RESOLUÇÃO-RDC No- 159, DE 2 DE JUNHO DE 2017. https://web.archive.org/web/20200116020728/http://portal.anvisa.gov.br/documents/33868/3233596/56+-+RDC+N%C2%BA+159-2017-DOU.pdf/27be30ee-3884-46fe-b7ba-ae2f94b74693. January 16, 2020. 1677-7042. Diário Official da União. Governo Federal do Brasil [Federal Government of Brazil]. pt. 103. N°106. May 23, 2017. June 5, 2017.
  25. Web site: Anlage NpSG. Bundesamt für Justiz [Federal Office of Justice]. December 10, 2019. de.
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  27. Web site: § 4 NpSG. Bundesamt für Justiz [Federal Office of Justice]. December 10, 2019. de.
  28. Web site: § 3 NpSG. Bundesamt für Justiz [Federal Office of Justice]. December 10, 2019. de.
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  30. Web site: Information Note-COM (2019) 631 Final. January 13, 2020. Controlled Drugs and Pharmacy Legislation Unit.
  31. Web site: 指定薬物一覧. December 27, 2019. 厚生労働省 [Ministry of Health, Labour and Welfare (MHLW)]. ja.
  32. Web site: 31 nya ämnen kan klassas som narkotika eller hälsofarlig vara. sv. October 17, 2020. June 21, 2016. Folkhälsomyndigheten [Public Health Agency of Sweden].
  33. Web site: Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien. Bundeskanzlei [Federal Chancellery of Switzerland]. January 1, 2020. de.
  34. Web site: Part II: Class B Drugs. Misuse of Drugs Act 1971. October 18, 2020. UK Government.
  35. 34291–34297. July 18, 2019. Temporary Placement of N-Ethylhexedrone, α-PHP, 4–MEAP, MPHP, PV8, and 4-Chloro-α-PVP in Schedule I. Federal Register. 84. 138. October 18, 2020. Drug Enforcement Administration (DEA).
  36. 32996–32999 . June 1, 2022 . 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. Federal Register. 87. 105. Drug Enforcement Administration (DEA).

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