Methiopropamine

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Methiopropamine
Methiopropamine-2d-skeletal.svg
Methiopropamine.png
Systematic (IUPAC) name
1-(thiophen-2-yl)-2-methylaminopropane
Legal status
Legal status
  • DE: Anlage I (Controlled)
  • UK: Temporary Class Drug
  • Illegal in China, Finland, Florida
Identifiers
CAS Number 801156-47-8 N
7464-94-0 (hydrochloride)
ATC code N06AA
PubChem CID 436156
ChemSpider 385727 YesY
Synonyms MPA; Methiopropamine; Methedrene; Syndrax
Chemical data
Formula C8H13NS
Molar mass 155.261 g/mol
 NYesY (what is this?)  (verify)

Methiopropamine (MPA) is a thiophene ring-based structural analog of methamphetamine originally reported in 1942.[1] Chemically it is not a phenethylamine or amphetamine and is not their functional analog either. It originally 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[edit]

Methiopropamine functions as a selective 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]

Metabolism[edit]

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.[5] Methiopropamine is metabolized into active thiopropamine, 4-hydroxymethiopropamine and thiophene S-oxides.[6][7] 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.[8][9]

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

Beside those pathways it shoud be mentioned that two drugs containing a thiophene ring were on the market, Tienilic acid and Suprofen, both have been withdrawn due to hepatotoxicity and cases of renal failure , this has been circumvened by introducing thiophene ring which is substituted in 4,5 positions. This may be due to sulfoxides and epoxide adducts that may interact with the GSH System and Methionine to form protein adducts.[10]

Synthesis[edit]

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.[11]

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

Legal status[edit]

China[edit]

As of October 2015 MPA is a controlled substance in China.[12]

Finland[edit]

Methiopropamine is illegal in Finland.[citation needed]

Germany[edit]

Methiopropamine is explicitly illegal in Germany.

United Kingdom[edit]

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[13] 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.[14]

United States[edit]

Methiopropamine is not scheduled at the federal level in the United States.[15]

Florida[edit]

Methiopropamine is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida.[16]

See also[edit]

References[edit]

  1. ^ Blicke, F. F.; Burckhalter, J. H. (1942). "α-Thienylaminoalkanes". Journal of the American Chemical Society 64 (3): 477–80. doi:10.1021/ja01255a001. 
  2. ^ Angelov, D; O'Brien, J; Kavanagh, P (2011). "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. 
  3. ^ Methiopropamine Thread at UKChemicalResearch.org
  4. ^ Iversen, L.; Gibbons, S.; Treble, R.; Setola, V.; Huang, X. P.; Roth, B. L. (2012). "Neurochemical profiles of some novel psychoactive substances". European Journal of Pharmacology. doi:10.1016/j.ejphar.2012.12.006. 
  5. ^ Vree, T.B.; Gorgels, J.P.M.C.; Muskens, A.Th.J.M.; Van Rossum, J.M. (1971). "Deuterium isotope effects in the metabolism of n-alkylsubstituted amphetamines in man". Clinica Chimica Acta 34 (2): 333–44. doi:10.1016/0009-8981(71)90187-2. PMID 5113570. 
  6. ^ Treiber, Alexander; Dansette, Patrick M.; El Amri, Hamid; Girault, Jean-Pierre; Ginderow, Daria; Mornon, Jean-Paul; Mansuy, Daniel (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. 
  7. ^ Dansette, P.M.; Thang, Do Cao; Mansuy, H. El Amri D.; Mansuy, D (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. 
  8. ^ Yamada, Hideyuki; Shiiyama, Sachiko; Soejimaohkuma, Toyomi; Honda, Shin-Ichiro; Kumagai, Yoshito; Cho, Arthur K.; Oguri, Kazuta; Yoshimura, Hidetoshi (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. 
  9. ^ Welter, J.; Meyer, M.R.; Wolf, E.U.; Weinmann, W.; Kavanaugh, P.; Maurer, H.H. (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): 3125–3135. doi:10.1007/s00216-013-6741-4. PMID 23361230. 
  10. ^ Smnith, G.F. (2011). Progress in Medicinal Chemistry 50: 6.  Missing or empty |title= (help); |chapter= ignored (help)
  11. ^ Casale, John F.; Hays, Patrick A. (2011). "Methiopropamine: An Analytical Profile" (PDF). Microgram Journal 8 (2): 53–7. 
  12. ^ "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. Retrieved 1 October 2015. 
  13. ^ 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. 
  14. ^ "The Misuse of Drugs Act 1971 (Temporary Class Drug) (No. 3) Order 2015". UK Government. 23 November 2015. 
  15. ^ 21 CFR — SCHEDULES OF CONTROLLED SUBSTANCES §1308.11 Schedule I.
  16. ^ Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL