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Methiopropamine

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Methiopropamine
Clinical data
Other namesMPA; N-Methylthiopropamine; Methiopropamine; Methedrene; Syndrax
ATC code
Legal status
Legal status
Identifiers
  • 1-(thiophen-2-yl)-2-methylaminopropane
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC8H13NS
Molar mass155.26 g·mol−1
3D model (JSmol)
  • CNC(C)CC1=CC=CS1
  • InChI=1S/C8H13NS/c1-7(9-2)6-8-4-3-5-10-8/h3-5,7,9H,6H2,1-2H3 checkY
  • Key:HPHUWHKFQXTZPS-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Methiopropamine (MPA), also known as N-methylthiopropamine, is an organic compound structurally related to methamphetamine.[2] Originally reported in 1942, the molecule consists of a thiophene group with an alkyl amine substituent at the 2-position.[2][3] It appeared for public sale in the United Kingdom in December 2010 as a "research chemical" or "legal high", recently branded as Blow.[4] It has limited popularity as a recreational stimulant.[2][5][unreliable source?]

Pharmacology

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Methiopropamine functions as a norepinephrine–dopamine reuptake inhibitor (NDRI) that is approximately 1.85 times more selective for norepinephrine than dopamine. It is approximately one-third as potent as dextroamphetamine as a norepinephrine reuptake inhibitor and one-fifth as much as a dopamine reuptake inhibitor. It displays negligible activity as a serotonin reuptake inhibitor.[6][7]

Methiopropamine has the potential for significant acute toxicity with cardiovascular, gastrointestinal, and psychotic symptoms.[8]

Metabolism

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Methiopropamine metabolism is somewhat similar to methamphetamine. Hydroxylation, demethylation and deamination are in common. Formation of thiophene S-oxide is different, as is the end product which will probably be (substituted) thiophene-2-carboxylic acid. It is then excreted in urine. Compounds on red are inactive.

For N-alkyl amphetamines, deamination and N-dealkylation are the major elimination pathways and renal excretion is a minor one.[9]

Methiopropamine is metabolized into active thiopropamine, 4-hydroxymethiopropamine and thiophene S-oxides.[10][11] These N-demethylated metabolites are further deaminated by the cytochrome P450 enzyme CYP2C19 in the liver transforming them into inactive 1-(thiophen-2-yl)-2-propan-2-one which can be seen as a phenylacetone derivative.[12][13]

Thiophene-2-carboxylic acid is the final major metabolic product. It is very hydrophilic and is excreted in urine. Methiopropamine and especially thiopropamine are also excreted renally, unchanged.

Synthesis

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There is a four-step synthesis of methiopropamine. It begins with (thiophen-2-yl)magnesium bromide, which is reacted with propylene oxide, yielding 1-(thiophen-2-yl)-2-hydroxypropane which is reacted with phosphorus tribromide, yielding 1-(thiophen-2-yl)-2-bromopropane which is finally reacted with methylamine, yielding 1-(thiophen-2-yl)-2-methylaminopropane.[14]

Four-step synthesis of racemic methiopropamine from (thiophen-2-yl)magnesium bromide.
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China

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As of October 2015 MPA is a controlled substance in China.[15]

Finland

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Methiopropamine is illegal in Finland, it is scheduled in "government decree on narcotic substances, preparations and plants".[16]

Germany

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Methiopropamine is explicitly illegal in Germany.

United Kingdom

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Following the ban on ethylphenidate, authorities noticed an increase in methiopropamine use by injecting users. The ACMD suggested it be banned on 18 November 2015[17] as it had similar effects to ethylphenidate. The government enacted a temporary drug control order a week later which came into force on 27 November 2015.[18] Though ordinarily the TCDO would only last 1 year, the ACMD reported that since its invocation prevalence of MPA had significantly decreased, and that it had been challenging to collect information about the drug. As a result of this, they requested that the TCDO be extended a further year.[19]

Methiopropanine was made a Class B controlled drug under the Misuse of Drugs Act 1971 (as amended) (Amendment)(No.2) Order 2017 [SI 2017/1114], this came into effect on the 27th of November 2017.

United States

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Methiopropamine is scheduled at the federal level in the United States.[20] The DEA had planned to place methiopropamine in Schedule I of Controlled Substances and was accepting public comments until October 4, 2021. Later, the compound was placed in Schedule I.[21]

Florida

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Methiopropamine is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida.[22]

Tasmania (Australia)

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Methiopropamine is a "controlled substance" and therefore an "illegal drug" to import, possess or sell/traffic in without express authority of the relevant government agency.

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. ^ a b c Bunaim MK, Damanhuri HA, Yow HY, Yaakob NS, Makmor-Bakry M, Azmi N (July 2024). "Understanding methiopropamine, a new psychoactive substance: an in-depth review on its chemistry, pharmacology and implications to human health". Int J Legal Med. 138 (4): 1295–1306. doi:10.1007/s00414-024-03201-7. PMID 38424369.
  3. ^ Blicke FF, Burckhalter JH (March 1942). "α-Thienylaminoalkanes". Journal of the American Chemical Society. 64 (3): 477–80. doi:10.1021/ja01255a001.
  4. ^ Angelov D, O'Brien J, Kavanagh P (March 2013). "The syntheses of 1-(2-thienyl)-2-(methylamino) propane (methiopropamine) and its 3-thienyl isomer for use as reference standards". Drug Testing and Analysis. 5 (3): 145–9. doi:10.1002/dta.298. PMID 21770051.
  5. ^ "Methiopropamine Thread". UKChemicalResearch.org. Archived from the original on 2015-07-04. Retrieved 2016-06-09.
  6. ^ Iversen L, Gibbons S, Treble R, Setola V, Huang XP, Roth BL (January 2013). "Neurochemical profiles of some novel psychoactive substances". European Journal of Pharmacology. 700 (1–3): 147–51. doi:10.1016/j.ejphar.2012.12.006. PMC 3582025. PMID 23261499.
  7. ^ Yoon HS, Cai WT, Lee YH, Park KT, Lee YS, Kim JH (September 2016). "The expression of methiopropamine-induced locomotor sensitization requires dopamine D2, but not D1, receptor activation in the rat". Behavioural Brain Research. 311: 403–407. doi:10.1016/j.bbr.2016.05.060. PMID 27265782. S2CID 46731570.
  8. ^ Lee HM, Wood DM, Hudson S, Archer JR, Dargan PI (September 2014). "Acute toxicity associated with analytically confirmed recreational use of methiopropamine (1-(thiophen-2-yl)-2-methylaminopropane)". Journal of Medical Toxicology. 10 (3): 299–302. doi:10.1007/s13181-014-0399-y. PMC 4141929. PMID 24706157.
  9. ^ Vree TB, Gorgels JP, Muskens AT, van Rossum JM (September 1971). "Deuterium isotope effects in the metabolism of N-alkylsubstituted amphetamines in man". Clinica Chimica Acta; International Journal of Clinical Chemistry. 34 (2): 333–44. doi:10.1016/0009-8981(71)90187-2. hdl:2066/142600. PMID 5113570.
  10. ^ Treiber A, Dansette PM, El Amri H, Girault J, Ginderow D, Mornon J, Mansuy D (1997). "Chemical and Biological Oxidation of Thiophene: Preparation and Complete Characterization of Thiophene S-Oxide Dimers and Evidence for Thiophene S-Oxide as an Intermediate in Thiophene Metabolism in Vivo and in Vitro". Journal of the American Chemical Society. 119 (7): 1565–71. doi:10.1021/ja962466g.
  11. ^ Dansette PM, Thang DC, el Amri H, Mansuy D (August 1992). "Evidence for thiophene-S-oxide as a primary reactive metabolite of thiophene in vivo: formation of a dihydrothiophene sulfoxide mercapturic acid". Biochemical and Biophysical Research Communications. 186 (3): 1624–30. doi:10.1016/S0006-291X(05)81594-3. PMID 1510686.
  12. ^ Yamada H, Shiiyama S, Soejima-Ohkuma T, Honda S, Kumagai Y, Cho AK, et al. (February 1997). "Deamination of amphetamines by cytochromes P450: studies on substrate specificity and regioselectivity with microsomes and purified CYP2C subfamily isozymes". The Journal of Toxicological Sciences. 22 (1): 65–73. doi:10.2131/jts.22.65. PMID 9076658.
  13. ^ Welter J, Meyer MR, Wolf EU, Weinmann W, Kavanagh P, Maurer HH (April 2013). "2-methiopropamine, a thiophene analogue of methamphetamine: studies on its metabolism and detectability in the rat and human using GC-MS and LC-(HR)-MS techniques". Analytical and Bioanalytical Chemistry. 405 (10): 3125–35. doi:10.1007/s00216-013-6741-4. PMID 23361230. S2CID 5470554.
  14. ^ Casale JF, Hays PA (2011). "Methiopropamine: An Analytical Profile" (PDF). Microgram Journal. 8 (2): 53–57.
  15. ^ "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in Chinese). China Food and Drug Administration. 27 September 2015. Archived from the original on 1 October 2015. Retrieved 1 October 2015.
  16. ^ https://finlex.fi/fi/laki/ajantasa/2008/20080543
  17. ^ Advisory Council on the Misuse of Drugs (25 November 2015). "Methiopropamine (MPA): A review of the evidence of use and harm" (PDF). UK Home Office. Retrieved 27 November 2015.
  18. ^ "The Misuse of Drugs Act 1971 (Temporary Class Drug) (No. 3) Order 2015". UK Government. 23 November 2015.
  19. ^ "Re: Temporary Class Drug Order on methiopropamine". 2016. Retrieved 2016-11-28.
  20. ^ "21 CFR — SCHEDULES OF CONTROLLED SUBSTANCES §1308.11 Schedule I." Archived from the original on 2009-08-27. Retrieved 2014-12-17.
  21. ^ "Federal Register". Federal Register. National Archives. December 9, 2022. Retrieved December 28, 2022.
  22. ^ Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL
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