Methiopropamine

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Methiopropamine
Methiopropamine-2d-skeletal.svg
Methiopropamine.png
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
Formula C8H13NS
Molar mass 155.26 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 Yes check.svgY
  • Key:HPHUWHKFQXTZPS-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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? ]

Contents

Pharmacology

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

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. Methiopropamine metabolism colored.png
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

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

China

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

Finland

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

Germany

Methiopropamine is explicitly illegal in Germany. [ citation needed ]

United Kingdom

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

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

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)

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. [ citation needed ]

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. 1 2 3 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. Bibcode:1942JAChS..64..477B. 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. Bibcode:1997JAChS.119.1565T. 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. Bibcode:1992BBRC..186.1624D. 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. ↑ finlex.fi
  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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