Chemistry:Methiopropamine

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Short description: Structural analog of methamphetamine
Methiopropamine
Methiopropamine-2d-skeletal.svg
Methiopropamine.png
Clinical data
Other namesMPA; Methiopropamine; Methedrene; Syndrax
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC8H13NS
Molar mass155.26 g·mol−1
3D model (JSmol)
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Methiopropamine (MPA) is an organic compound structurally related to methamphetamine. Originally reported in 1942, the molecule consists of a thiophene group with an alkyl amine substituent at the 2-position.[1] It appeared for public sale in the UK in December 2010 as a "research chemical" or "legal high", recently branded as Blow.[2] It has limited popularity as a recreational stimulant.[3][unreliable source?]

Pharmacology

Methiopropamine functions as a norepinephrine-dopamine reuptake inhibitor 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.[4][5]

Methiopropamine has the potential for significant acute toxicity with cardiovascular, gastrointestinal, and psychotic symptoms.[6]

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.

For N-alkyl amphetamines, deamination and N-dealkylation are the major elimination pathways and renal excretion is a minor one.[7]

Methiopropamine is metabolized into active thiopropamine, 4-hydroxymethiopropamine and thiophene S-oxides.[8][9] 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.[10][11]

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.[12]

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

Legal status

China

As of October 2015 MPA is a controlled substance in China.[13]

Finland

Methiopropamine is illegal in Finland.[citation needed]

Germany

Methiopropamine is explicitly illegal in Germany.

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[14] 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.[15] 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.[16]

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 .[17] 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.[18]

Florida

Methiopropamine is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida.[19]

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.

See also

References

  1. ↑ "α-Thienylaminoalkanes". Journal of the American Chemical Society 64 (3): 477–80. March 1942. doi:10.1021/ja01255a001. 
  2. ↑ "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. March 2013. doi:10.1002/dta.298. PMID 21770051. 
  3. ↑ "Methiopropamine Thread". UKChemicalResearch.org. https://www.ukchemicalresearch.org/Thread-MPA. 
  4. ↑ "Neurochemical profiles of some novel psychoactive substances". European Journal of Pharmacology 700 (1–3): 147–51. January 2013. doi:10.1016/j.ejphar.2012.12.006. PMID 23261499. 
  5. ↑ "The expression of methiopropamine-induced locomotor sensitization requires dopamine D2, but not D1, receptor activation in the rat". Behavioural Brain Research 311: 403–407. September 2016. doi:10.1016/j.bbr.2016.05.060. PMID 27265782. 
  6. ↑ "Acute toxicity associated with analytically confirmed recreational use of methiopropamine (1-(thiophen-2-yl)-2-methylaminopropane)". Journal of Medical Toxicology 10 (3): 299–302. September 2014. doi:10.1007/s13181-014-0399-y. PMID 24706157. 
  7. ↑ "Deuterium isotope effects in the metabolism of N-alkylsubstituted amphetamines in man". Clinica Chimica Acta; International Journal of Clinical Chemistry 34 (2): 333–44. September 1971. doi:10.1016/0009-8981(71)90187-2. PMID 5113570. 
  8. ↑ "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. 1997. doi:10.1021/ja962466g. 
  9. ↑ "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. August 1992. doi:10.1016/S0006-291X(05)81594-3. PMID 1510686. 
  10. ↑ "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. February 1997. doi:10.2131/jts.22.65. PMID 9076658. 
  11. ↑ "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. April 2013. doi:10.1007/s00216-013-6741-4. PMID 23361230. https://boris.unibe.ch/44923/. 
  12. ↑ "Methiopropamine: An Analytical Profile". Microgram Journal 8 (2): 53–57. 2011. https://www.justice.gov/dea/pr/microgram-journals/2011/mj8-2_53-57.pdf. 
  13. ↑ "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. http://www.sfda.gov.cn/WS01/CL0056/130753.html. 
  14. ↑ Advisory Council on the Misuse of Drugs (25 November 2015). "Methiopropamine (MPA): A review of the evidence of use and harm". UK Home Office. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/479996/23_November_-_TCDO_Report_for_MPA.pdf. 
  15. ↑ "The Misuse of Drugs Act 1971 (Temporary Class Drug) (No. 3) Order 2015". UK Government. 23 November 2015. http://www.legislation.gov.uk/uksi/2015/1929/made. 
  16. ↑ "Re: Temporary Class Drug Order on methiopropamine". 2016. https://www.gov.uk/government/publications/temporary-class-drug-order-on-methiopropamine. 
  17. ↑ "21 CFR — SCHEDULES OF CONTROLLED SUBSTANCES §1308.11 Schedule I.". http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_11.htm. 
  18. ↑ "Federal Register". National Archives. December 9, 2022. https://www.federalregister.gov/agencies/drug-enforcement-administration. 
  19. ↑ Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL



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