Substituted cathinone

Substituted cathinones, which include some stimulants and entactogens, are derivatives of cathinone. They feature a phenethylamine core with an alkyl group attached to the alpha carbon, and a ketone group attached to the beta carbon, along with additional substitutions.[1][2][3][4][5][6] Cathinone occurs naturally in the plant khat whose leaves are chewed as a recreational drug.[7]

General chemical structure of substituted cathinones, with R1-R4 defined in text

List of substituted cathinones

The derivatives may be produced by substitutions at four locations of the cathinone molecule:

  • R1 = hydrogen, or any combination of one or more alkyl, alkoxy, alkylenedioxy, haloalkyl or halide substituents
  • R2 = hydrogen or any alkyl group
  • R3 = hydrogen, any alkyl group, or incorporation in a cyclic structure
  • R4 = hydrogen, any alkyl group, or incorporation in a cyclic structure

The following table displays notable derivatives that have been reported:

Compound R1 R2 R3 R4
CathinoneHMeHH
MethcathinoneHMeHMe
EthcathinoneHMeHEt
PropylcathinoneHMeHnPr
BuphedroneHEtHMe
NEBHEtHEt
N-methyl-N-ethylbuphedroneHEtMeEt
PentedroneHnPrHMe
N-EthylpentedroneHnPrHEt
N-IsopropylpentedroneHnPrHiPr
HexedroneHnBuHMe
Ethyl-HexedroneHnBuHEt
N-Isobutylhexedrone (NDH)HnBuHi-Bu
IsohexedroneHiBuHMe
OctedroneHhexylHMe
DimethylcathinoneHMeMeMe
DiethylpropionHMeEtEt
N-methyl-N-ethylcathinoneHMeMeEt
Bupropion (3-CBP)3-ClMeHt-Bu
Hydroxybupropion3-ClMeH2-methyl-3-OH-propan-2-yl
Mephedrone4-MeMeHMe
2-MMC2-MeMeHMe
2-MEC2-MeMeHEt
2-EEC2-EtMeHEt
3-MMC3-MeMeHMe
3-MEC3-MeMeHEt
3-EMC3-EtMeHMe
3-EEC3-EtMeHEt
4-EMC4-EtMeHMe
4-EEC4-EtMeHEt
4-MC4-MeMeHH
Benzedrone4-MeMeHBn
2'-MeO-Benzedrone4-MeMeH2-MeO-Bn
4-MEC4-MeMeHEt
4-MPC4-MeMeHnPr
N,N-DMMC4-MeMeMeMe
N,N-MEMC4-MeMeMeEt
N,N-DEMC4-MeMeEtEt
4-MEAP4-MePrHEt
EDMC4-EtMeMeMe
2,4-DMMC2,4-dimethylMeHMe
2,4-DMEC2,4-dimethylMeHEt
3,4-DMMC3,4-dimethylMeHMe
3,4-DMEC3,4-dimethylMeHEt
2,4,5-TMMC2,4,5-trimethylMeHMe
2,4,5-TMOMC2,4,5-trimethoxyMeHMe
3,4,5-TMOMC3,4,5-trimethoxyMeHMe
Methedrone4-MeOMeHMe
Dimethedrone4-MeOMeMeMe
Ethedrone4-MeOMeHEt
2-MOMC2-MeOMeHMe
3-MOMC3-MeOMeHMe
3-FC3-FMeHH
4-FC4-FMeHH
2-FMC2-FMeHMe
2-FEC2-FMeHEt
3-FMC3-FMeHMe
3-FEC3-FMeHEt
2-CMC2-ClMeHMe
2-BMC2-BrMeHMe
2-IMC2-IMeHMe
2-TFMAP2-CF3MeHMe
Clophedrone3-ClMeHMe
3-CEC3-ClMeHEt
3-BMC3-BrMeHMe
3-IMC3-IMeHMe
3-TFMAP3-CF3MeHMe
Flephedrone4-FMeHMe
4-FEC4-FMeHEt
Clephedrone4-ClMeHMe
4-CEC4-ClMeHEt
4-CiPC4-ClMeHiPr
4-CBC4-ClMeHnBu
4-CDMC4-ClMeMeMe
Brephedrone4-BrMeHMe
4-BEC4-BrMeHEt
4-IMC4-IMeHMe
4-TFMAP4-CF3MeHMe
4-EFMC4-(2-fluoroethyl)MeHMe
4-MTMC4-SCH3MeHMe
4-MSMC4-SO2CH3MeHMe
4-PHMC4-phenylMeHMe
Mexedrone4-MemethoxymethylHMe
FMMC3-F-4-MeMeHMe
MFMC3-Me-4-FMeHMe
MMOMC3-Me-4-MeOMeHMe
3,4-DCMC3,4-dichloroMeHMe
3,5-DCMC3,5-dichloroMeHMe
3,5-DFMC3,5-difluoroMeHMe
2,5-DMOMC2,5-dimethoxyMeHMe
βk-2C-C2,5-dimethoxy-4-chloroHHH
βk-2C-B2,5-dimethoxy-4-bromoHHH
βk-2C-I2,5-dimethoxy-4-iodoHHH
βk-2C-D2,5-dimethoxy-4-methylHHH
βk-2C-E2,5-dimethoxy-4-ethylHHH
βk-2C-P2,5-dimethoxy-4-propylHHH
βk-2C-iP2,5-dimethoxy-4-isopropylHHH
βk-DOB2,5-dimethoxy-4-bromoMeHH
βk-MDOM2,5-dimethoxy-4-methylMeHMe
βk-MDA3,4-methylenedioxyMeHH
N-acetyl-βk-MDA3,4-methylenedioxyMeHacetyl
2,3-MDMC2,3-methylenedioxyMeHMe
Methylone3,4-methylenedioxyMeHMe
Dimethylone3,4-methylenedioxyMeMeMe
N-acetyl-methylone3,4-methylenedioxyMeacetylMe
N-hydroxy-methylone3,4-methylenedioxyMehydroxyMe
Ethylone3,4-methylenedioxyMeHEt
Diethylone3,4-methylenedioxyMeEtEt
N-acetyl-ethylone3,4-methylenedioxyMeacetylEt
N-isopropyl-βk-MDA3,4-methylenedioxyMeHiPr
MDPT3,4-methylenedioxyMeHt-Bu
BMDP3,4-methylenedioxyMeHBn
3,4-EDMC3,4-ethylenedioxyMeHMe
βk-IMP3,4-trimethyleneMeHMe
βk-IBP3,4-trimethyleneEtHEt
βk-IVP3,4-trimethylenenPrHEt
3-Fluorobuphedrone3-FEtHMe
4-Fluorobuphedrone4-FEtHMe
4-Bromobuphedrone4-BrEtHMe
4-MeMABP4-MeEtHMe
4-Me-NEB4-MeEtHEt
4-F-NEB4-FEtHEt
4-Me-DMB4-MeEtMeMe
3,4-DMEB3,4-dimethylEtHEt
4-Methoxybuphedrone4-MeOEtHMe
Butylone3,4-methylenedioxyEtHMe
Eutylone3,4-methylenedioxyEtHEt
βk-PBDB3,4-methylenedioxyEtHnPr
Bn-4-MeMABP4-MeEtHBn
BMDB3,4-methylenedioxyEtHBn
βk-DMBDB3,4-methylenedioxyEtMeMe
βk-MMDMA3,4-methylenedioxy-5-MeOMeHMe
βk-MMDMA-22-MeO-3,4-methylenedioxyMeHMe
βk-DMMDA2,5-diMeO-3,4-methylenedioxyMeHH
5-Methylmethylone3,4-methylenedioxy-5-MeMeHMe
5-Methylethylone3,4-methylenedioxy-5-MeMeHEt
2-Methylbutylone2-Me-3,4-methylenedioxyEtHMe
5-Methylbutylone3,4-methylenedioxy-5-MeEtHMe
Pentylone3,4-methylenedioxynPrHMe
N-Ethylpentylone3,4-methylenedioxynPrHEt
N-propylpentylone3,4-methylenedioxynPrHnPr
Dipentylone3,4-methylenedioxynPrMeMe
Hexylone3,4-methylenedioxynBuHMe
NEH3,4-methylenedioxynBuHEt
4-MEAP4-MenPrHEt
3,4-DMEP3,4-dimethylnPrHEt
4-F-Pentedrone4-FnPrHMe
4-Cl-Pentedrone4-ClnPrHMe
4-Methylpentedrone4-MenPrHMe
DL-46623,4-dimethoxynPrHEt
4-F-iPr-norpentedrone4-FnPrHiPr
3-CBV3-ClnPrHtBu
4-methylhexedrone4-MenBuHMe
MEH4-MenBuHEt
4-F-hexedrone4-FnBuHMe
4-F-octedrone4-FhexylHMe
α-phenylmephedrone4-MephenylHMe
βk-EphenidineHphenylHEt
"NRG-3"β-naphthyl instead of phenylMeHMe
βk-Methiopropaminethiophen-2-yl instead of phenylMeHMe
βk-5-MAPBbenzofuran-5-yl instead of phenylMeHMe
βk-6-MAPBbenzofuran-6-yl instead of phenylMeHMe
βk-5-ITindol-5-yl instead of phenylMeHH
α-PhthalimidopropiophenoneHMephthalimido
PPPOHMepiperidinyl
PPBOHEtpiperidinyl
FPPVO4-FnPrpiperidinyl
MDPV-azepane3,4-methylenedioxynPrazepane
Caccure 9074-SCH3α,α-di-Memorpholinyl
α-PPPHMepyrrolidinyl
α-PBPHEtpyrrolidinyl
α-PVP (O-2387)HnPrpyrrolidinyl
α-PHPHnBupyrrolidinyl
α-PHiPHiBupyrrolidinyl
α-PEP (α-PHPP)HnPepyrrolidinyl
α-POPHhexylpyrrolidinyl
α-PNPHheptylpyrrolidinyl
DPPEHphenylpyrrolidinyl
α-PcPePHcyclopentylpyrrolidinyl
α-PCYPHcyclohexylpyrrolidinyl
2-MePPP2-MeMepyrrolidinyl
3-MePPP3-MeMepyrrolidinyl
4-MePPP4-MeMepyrrolidinyl
MOPPP4-MeOMepyrrolidinyl
3-F-PPP3-FMepyrrolidinyl
FPPP4-FMepyrrolidinyl
Cl-PPP4-ClMepyrrolidinyl
2,4-DMPPP2,4-dimethylMepyrrolidinyl
MPBP4-MeEtpyrrolidinyl
FPBP4-FEtpyrrolidinyl
3-MPBP3-MeEtpyrrolidinyl
3-F-PBP3-FEtpyrrolidinyl
EPBP4-EtEtpyrrolidinyl
MOPBP4-MeOEtpyrrolidinyl
O-23843,4-dichloroEtpyrrolidinyl
Pyrovalerone (O-2371)4-MenPrpyrrolidinyl
3-F-PVP3-FnPrpyrrolidinyl
FPVP4-FnPrpyrrolidinyl
4-Cl-PVP4-ClnPrpyrrolidinyl
4-Br-PVP4-BrnPrpyrrolidinyl
MOPVP4-MeOnPrpyrrolidinyl
DMOPVP3,4-dimethoxynPrpyrrolidinyl
DMPVP3,4-dimethylnPrpyrrolidinyl
O-23903,4-dichloronPrpyrrolidinyl
MPHP4-MenBupyrrolidinyl
FPHP4-FnBupyrrolidinyl
4-Cl-PHP4-ClnBupyrrolidinyl
DMOPHP3,4-dimethoxynBupyrrolidinyl
3F-PiHP3-FiBupyrrolidinyl
4F-PiHP4-FiBupyrrolidinyl
O-24944-MeiBupyrrolidinyl
MPEP4-Mepentylpyrrolidinyl
4F-PV84-Fpentylpyrrolidinyl
4-MeO-PV84-MeOpentylpyrrolidinyl
4F-PV94-Fhexylpyrrolidinyl
4-MeO-PV94-MeOhexylpyrrolidinyl
α-Phenylpyrovalerone4-Mephenylpyrrolidinyl
MDPPP3,4-methylenedioxyMepyrrolidinyl
MDMPP3,4-methylenedioxyα,α-di-Mepyrrolidinyl
MDPBP3,4-methylenedioxyEtpyrrolidinyl
MDPV3,4-methylenedioxynPrpyrrolidinyl
2,3-MDPV2,3-methylenedioxynPrpyrrolidinyl
5-Me-MDPV3,4-methylenedioxy-5-MenPrpyrrolidinyl
6-Me-MDPV2-Me-4,5-methylenedioxynPrpyrrolidinyl
6-MeO-MDPV2-MeO-4,5-methylenedioxynPrpyrrolidinyl
Br-MeO-MDPV2,3-methylenedioxy-4-MeO-5-BrnPrpyrrolidinyl
MDPiVP3,4-methylenedioxyiPrpyrrolidinyl
MDPHP3,4-methylenedioxynBupyrrolidinyl
MDPEP (MD-PV8)3,4-methylenedioxypentylpyrrolidinyl
MDPOP (MD-PV9)3,4-methylenedioxyhexylpyrrolidinyl
5-PPDI3,4-trimethyleneEtpyrrolidinyl
5-BPDI3,4-trimethylenenPrpyrrolidinyl
5-HPDI3,4-trimethylenenBupyrrolidinyl
IPPV3,4-trimethylenephenylpyrrolidinyl
TH-PVP3,4-tetramethylenenPrpyrrolidinyl
TH-PHP3,4-tetramethylenenBupyrrolidinyl
5-DBFPV2,3-dihydrobenzofuran-5-yl instead of PhnPrpyrrolidinyl
3-BF-PVPbenzofuran-3-yl instead of PhnPrpyrrolidinyl
Naphyrone (O-2482)β-naphthyl instead of phenylnPrpyrrolidinyl
α-Naphyroneα-naphthyl instead of phenylnPrpyrrolidinyl
α-PPTthiophen-2-yl instead of phenylMepyrrolidinyl
α-PBTthiophen-2-yl instead of phenylEtpyrrolidinyl
α-PVTthiophen-2-yl instead of phenylnPrpyrrolidinyl

Legality

On 2 April 2010, the Advisory Council on the Misuse of Drugs in the UK announced that a broad structure-based ban of this entire class of compounds would be instituted, following extensive publicity around grey-market sales and recreational use of mephedrone, a common member of the family. This ban covers compounds with the aforementioned general structure, with 28 compounds specifically named.[8]

Any compound (not being bupropion or a substance for the time being specified in paragraph 2.2) structurally derived from 2-amino-1-phenyl-1-propanone by modification in any of the following ways, that is to say,

(i) by substitution in the phenyl ring to any extent with alkyl, alkoxy, alkylenedioxy, haloalkyl or halide substituents, whether or not further substituted in the phenyl ring by one or more other univalent substituents;

(ii) by substitution at the 3-position with an alkyl substituent;

(iii) by substitution at the nitrogen atom with alkyl or dialkyl groups, or by inclusion of the nitrogen atom in a cyclic structure.

ACMD, 2 April 2010

This text was added as an amendment to the Misuse of Drugs Act 1971, to come into force on 16 April 2010.[9] Note that four of the above compounds (cathinone, methcathinone, diethylpropion and pyrovalerone) were already illegal in the UK at the time the ACMD report was issued. Two compounds were specifically excluded from the ban, these being bupropion because of its common use in medicine and relative lack of abuse potential, and naphyrone because its structure falls outside the generic definition and not enough evidence was yet available to justify a ban.

Naphyrone analogues were subsequently banned in July 2010 following a further review by the ACMD,[10][11] along with a further broad based structure ban even more expansive than the last.[12][13]

“Any compound structurally derived from 2–aminopropan–1–one by substitution at the 1-position with any monocyclic, or fused-polycyclic ring system (not being a phenyl ring or alkylenedioxyphenyl ring system), whether or not the compound is

further modified in any of the following ways, that is to say—

(i) by substitution in the ring system to any extent with alkyl, alkoxy, haloalkyl or halide substituents, whether or not further substituted in the ring system by one or more other univalent substituents;

(ii) by substitution at the 3–position with an alkyl substituent;

(iii) by substitution at the 2-amino nitrogen atom with alkyl or dialkyl groups, or

by inclusion of the 2-amino nitrogen atom in a cyclic structure.”

Home Office, 13 July 2010.
General chemical structure of substituted naphyrones, with R1-R3 defined in text

The substitutions in the general structure for naphyrone analogues subject to the ban may be described as follows:

  • Cyc = any monocyclic, or fused-polycyclic ring system (not being a phenyl ring or alkylenedioxyphenyl ring system), including analogues where the ring system is substituted to any extent with alkyl, alkoxy, haloalkyl or halide substituents, whether or not further substituted in the ring system by one or more other univalent substituents
  • R1 = hydrogen or any alkyl group
  • R2 = hydrogen, any alkyl group, or incorporation in a cyclic structure
  • R3 = hydrogen, any alkyl group, or incorporation in a cyclic structure

More new derivatives have however continued to appear, with the UK reporting more novel cathinone derivatives detected in 2010 than any other country in Europe, with most of them first identified after the generic ban had gone into effect and thus already being illegal despite never having been previously reported.[14]

In the United States, substituted cathinones are the psychoactive ingredients in "bath salts" which as of July 2011 were banned by at least 28 states, but not by the federal government.[15]

See also

References

  1. Meltzer PC, Butler D, Deschamps JR, Madras BK. 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem. 2006 Feb 23;49(4):1420-32. PMID 16480278 doi:10.1021/jm050797a
  2. Paillet-Loilier M, Cesbron A, Le Boisselier R, Bourgine J, Debruyne D. Emerging drugs of abuse: current perspectives on substituted cathinones. Subst Abuse Rehabil. 2014; 5: 37-52. PMID 24966713 doi:10.2147/SAR.S37257
  3. Simmons SJ, Leyrer-Jackson JM, Oliver CF, Hicks C, Muschamp JW, Rawls SM, Olive MF. DARK Classics in Chemical Neuroscience: Cathinone-Derived Psychostimulants. ACS Chem. Neurosci. 2018; 9(10): 2379-2394. PMID 29714473 doi:10.1021/acschemneuro.8b00147
  4. Beck O, Bäckberg M, Signell P, Helander A. Intoxications in the STRIDA project involving a panorama of psychostimulant pyrovalerone derivatives, MDPV copycats. Clin Toxicol (Phila). 2018 Apr;56(4):256-263. PMID 28895757 doi:10.1080/15563650.2017.1370097
  5. Majchrzak M, Celiński R, Kuś P, Kowalska T, Sajewicz M. The newest cathinone derivatives as designer drugs: an analytical and toxicological review. Forensic Toxicol. 2018;36(1):33-50. PMID 29367861 doi:10.1007/s11419-017-0385-6
  6. Błażewicz, A., Bednarek, E., Popławska, M. et al. Identification and structural characterization of synthetic cathinones: N-propylcathinone, 2,4-dimethylmethcathinone, 2,4-dimethylethcathinone, 2,4-dimethyl-α-pyrrolidinopropiophenone, 4-bromo-α-pyrrolidinopropiophenone, 1-(2,3-dihydro-1H-inden-5-yl)-2-(pyrrolidin-1-yl)hexan-1-one and 2,4-dimethylisocathinone. Forensic Toxicol 2019; 37: 288-307. doi:10.1007/s11419-018-00463-w
  7. Colzato LS, Ruiz MJ, van den Wildenberg WP, Hommel B. Khat use is associated with impaired working memory and cognitive flexibility. PLoS One. 2011;6(6):e20602. PMID 21698275. Retrieved 2011-07-17.
  8. Advisory Council on the Misuse of Drugs (UK). Consideration of the cathinones. 31 March 2010. Archived 22 September 2011 at the Wayback Machine Retrieved 2011-07-17.
  9. "The Misuse of Drugs (Amendment) (England, Wales and Scotland) Regulations 2010 No. 1144". Opsi.gov.uk. Retrieved 8 April 2010.
  10. "NRG-1 'legal high' drug is banned". BBC News. 12 July 2010. Retrieved 17 July 2010.
  11. "Advisory Council on the Misuse of Drugs Naphyrone Report (2010)". Home Office. 7 July 2010. Archived from the original on 17 July 2010. Retrieved 17 July 2010.
  12. "Explanatory Memorandum To The Misuse of Drugs (Amendment No. 2) (England, Wales and Scotland) Regulations 2010 No. 1799" (PDF). Opsi.gov.uk. Retrieved 18 July 2010.
  13. "The Misuse of Drugs (Amendment No. 2) (England, Wales and Scotland) Regulations 2010 No. 1799" (PDF). Opsi.gov.uk. Retrieved 18 July 2010.
  14. European Monitoring Centre on Drugs and Drug Addiction. EMCDDA–Europol 2010 Annual Report on the implementation of Council Decision 2005/387/JHA. Retrieved 2011-07-17.
  15. Goodnough A, Zezima K. An Alarming New Stimulant, Legal in Many States. New York Times 2011 July 16. Retrieved 2011-07-17.
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