4-Methylthioamphetamine

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4-Methylthioamphetamine
4-methylthioamphetamine.svg
4-MTA-3D-vdW.png
Legal status
Legal status
Identifiers
  • 1-[4-(Methylsulfanyl)phenyl]propan-2-amine
CAS Number
PubChem CID
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KEGG
ChEMBL
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Chemical and physical data
Formula C10H15NS
Molar mass 181.30 g·mol−1
3D model (JSmol)
  • NC(C)CC(C=C1)=CC=C1SC
  • InChI=1S/C10H15NS/c1-8(11)7-9-3-5-10(12-2)6-4-9/h3-6,8H,7,11H2,1-2H3 Yes check.svgY
  • Key:OLEWMKVPSUCNLG-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

4-Methylthioamphetamine (4-MTA) is a designer drug of the substituted amphetamine class developed in the 1990s by a team led by David E. Nichols, an American pharmacologist and medical chemist, at Purdue University. It acts as a non-neurotoxic highly selective serotonin releasing agent (SSRA) in animals. [2] [3] [4] 4-MTA is the methylthio derivative of amphetamine.

Contents

History

First appearance

In 1997, the Forensic Science Laboratory of the Netherlands received reports of three unrelated drug deaths. The substance in question was a new ring-substituted amphetamine derivative. In 1998 two additional cases of this still unknown compound were added to the list, and the incidents were reported to the IPSC (Institut de Police Scientifique et de Criminologie, University of Lausanne, Switzerland). [5] In both the Netherlands and Switzerland, the unknown compound was encountered in the hydrochloride salt form, and pictures of the different tablets were compared to each other. After an investigation, it appeared that in other European countries such as the United Kingdom and Germany the derivative was also encountered. The new drug even got as far as Australia. After analytical research, the compound was identified as 4-methylthioamphetamine (4-MTA). This was an already known compound originally only intended for pharmacological studies on animals. The studies of 4-MTA by David Nichols were then linked to the tablets found in all the different countries.

Development

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. 4-MTA was ranked 12th in dependence, 10th in physical harm, and 17th in social harm. Rational harm assessment of drugs radar plot.svg
Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. 4-MTA was ranked 12th in dependence, 10th in physical harm, and 17th in social harm.

4-MTA was developed by the research team led by David Nichols [2] but was intended to be used only as an agent for laboratory research into the serotonin transporter protein. Nichols was reportedly sad to see 4-MTA appear as a drug of abuse on the street. He said after finding out his research was used as a dangerous serotonin releasing drugs, "I was stunned. I had published information ultimately led to human death." [7] Nichols intentions were to discover how MDMA worked in the brain to eventually find a positive use for it in psychotherapy. Nichols studied thereby molecules with similar structure, including 4-MTA. Between 1992 and 1997 they published three papers on the effects of this drug in rats and the idea that it could potentially be used in the treatment of depression and be a potential replacement for Prozac. Without the knowledge of Nichols and his team, others synthesized the drugs into a tablet. These tablets were known by their street name, 'flatliners'. Nichols' laboratory had published that the rats perceived the effects of 4-MTA to be like those of ecstasy, which was probably the motivation for its production and distribution to humans. [7] Nichols also said, "I have never considered my research to be dangerous, and in fact hoped one day to develop medicines to help people." [7] Because of the 4-MTA relating death, Nichols' laboratory was asked to study the human effects of other materials they have studied, to avoid likewise situation as with 4-MTA. Most of the molecules the laboratory further had published could not kill in reasonable dosages.

Use and availability

The typical tablets sold on the street contained approximately between 100–140 mg 4-MTA. [8] 4-MTA was briefly sold in smart shops in the Netherlands, though was soon banned by the Dutch government after serious side-effects started to emerge. The Union of Smartshop Owners decided to leave it out of their assortment after they discovered the drug had only been tested on rats. [9] It was also briefly sold on the black market as MDMA during the late 1990s, mainly in the US, but proved unpopular due to its high risk of severe side effects (several deaths were reported) and relative lack of positive euphoria. [10]

Effects

4-MTA is a strong serotonin releaser similar to paramethoxyamphetamine (PMA), which can cause pronounced hyperthermia potentially resulting in organ failure and death. [11] [12] [13] [14] [ better source needed ] Therefore, the major neuropharmacological effect is an increased release of serotonin, and the inhibition of serotonin uptake of mono oxidase A (MAO-A). The combination of the releasing of serotonin from neurons, but the prevention of breaking this neurotransmitter down again, leads to dangerous serotonin syndrome. The serotonin syndrome is a hyper serotonergic state, which can become fatal and is a side effect of serotonergic enhancing drugs. The symptoms of serotonin syndrome caused by 4-MTA are described in the Report on the Risk Assessment of 4-MTA

Symptoms of the serotonin syndrome caused by 4-MTA

[15] Another effect is the increase of the secretion of several hormones, like adrenocorticotropic hormone (ACTH), corticosterone, prolactin, oxytocin, and renin induced by 4-MTA through stimulation of serotonergic neurotransmission.

There has been suggested that 4-MTA because of its slow onset of action, is more dangerous than other designer drugs. Users of the drug rapidly take another dose because they assume the first was inadequate; thus increasing the possibility of an overdose. (EMCDDA, 1999)

Today the knowledge about the effects of 4-MTA is narrow, because of very limited research and experimental data. The only 4 studies that are conducted show a weak effect on dopamine and noradrenaline. This study was executed with a single dose of 4-MTA, no study where the effect of multiple doses 4-MTA where researched exist up to date.[ citation needed ]

Pharmacology

4-MTA is a potent monoamine oxidase A (MAO-A) inhibitor. [16] Its IC50 Tooltip half-maximal inhibitory concentration for MAO-A inhibition has been reported to be 250 nM. [16]

Chemistry

In a procedure analogous to the production of other amphetamines, 4-MTA has been prepared from 4-(methylthio)phenylacetone by the Leuckart reaction and the reaction byproducts have been characterized. [17]

Metabolism

How 4-MTA is metabolized by rats Metabolism 4-MTA.jpg
How 4-MTA is metabolized by rats

4-MTA undergoes limited biotransformation, the metabolic pathways of the metabolites in humans is postulated in the following steps:

  1. β-Hydroxylation of the side chain to 4-hydroxy-4-methylthioamphetamine (step I).
  2. Ring hydroxylation to a phenolic structure (step II).
  3. Oxidative deamination to form an oxo metabolite, followed by (step III):
    • reduction into the corresponding alcohol (step IIIa),
    • degradation of the side chain to 4-methylthiobenzoic acid (step IIIb). [18]

The main metabolite was identified as 4-methylthiobenzoic acid. This compound leads to bioactivation (toxification), since the metabolite increases dramatically the sensitivity to the reduction in ATP content. [19] The biotransformation shows great similarities to the metabolic pathway of the structurally related 4-methoxyamphetamine [18]

See also

Related Research Articles

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<i>para</i>-Methoxyamphetamine Chemical compound

para-Methoxyamphetamine (PMA), also known as 4-methoxyamphetamine (4-MA), is a designer drug of the amphetamine class with serotonergic effects. Unlike other similar drugs of this family, PMA does not produce stimulant, euphoriant, or entactogen effects, and behaves more like an antidepressant in comparison, though it does have some psychedelic properties.

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<span class="mw-page-title-main">4-Fluoroamphetamine</span> Psychoactive research chemical

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<i>para</i>-Methoxy-<i>N</i>-methylamphetamine Stimulant and psychedelic designer drug

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<i>para</i>-Chloroamphetamine Chemical compound

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<span class="mw-page-title-main">Serotonin releasing agent</span> Class of compounds

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<span class="mw-page-title-main">3-Methoxyamphetamine</span> Stimulant drug of the amphetamine class

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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 Huang X, Marona-Lewicka D, Nichols DE (December 1992). "p-methylthioamphetamine is a potent new non-neurotoxic serotonin-releasing agent". European Journal of Pharmacology. 229 (1): 31–38. doi:10.1016/0014-2999(92)90282-9. PMID   1473561.
  3. ↑ Li Q, Murakami I, Stall S, Levy AD, Brownfield MS, Nichols DE, Van de Kar LD (December 1996). "Neuroendocrine pharmacology of three serotonin releasers: 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAi) and p-methylthioamphetamine (MTA)". The Journal of Pharmacology and Experimental Therapeutics. 279 (3): 1261–1267. PMID   8968349.
  4. ↑ Murphy J, Flynn JJ, Cannon DM, Guiry PJ, McCormack P, Baird AW, et al. (May 2002). "In vitro neuronal and vascular responses to 5-hydroxytryptamine: modulation by 4-methylthioamphetamine, 4-methylthiomethamphetamine and 3,4-methylenedioxymethamphetamine". European Journal of Pharmacology. 444 (1–2): 61–67. doi:10.1016/S0014-2999(02)01586-8. PMID   12191583.
  5. ↑ Poortman AJ, Lock E (March 1999). "Analytical profile of 4-methylthioamphetamine (4-MTA), a new street drug". Forensic Science International. 100 (3): 221–233. doi:10.1016/S0379-0738(98)00214-X. PMID   10423848.
  6. ↑ Nutt D, King LA, Saulsbury W, Blakemore C (March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse". Lancet. 369 (9566): 1047–1053. doi:10.1016/s0140-6736(07)60464-4. PMID   17382831. S2CID   5903121.
  7. 1 2 3 Nichols D (January 2011). "Legal highs: the dark side of medicinal chemistry". Nature. 469 (7328): 7. Bibcode:2011Natur.469....7N. doi: 10.1038/469007a . PMID   21209630.
  8. ↑ Błachut D, Wojtasiewicz K, Czarnocki Z, Szukalski B (November 2009). "The analytical profile of some 4-methylthioamphetamine (4-MTA) homologues". Forensic Science International. 192 (1–3): 98–114. doi:10.1016/j.forsciint.2009.08.009. PMID   19766415.
  9. ↑ "Report on the Risk Assessment of 4-MTA in the Framework of the Joint Action on New Synthetic Drugs" (PDF). Joint Action on New Synthetic Drugs : 8. 1999-05-19. Archived (PDF) from the original on 2020-09-18. Retrieved 2022-08-21– via European Monitoring Centre for Drugs and Drug Addiction.
  10. ↑ "Ecstasy Or MDMA (also Known As Molly)". www.dea.gov. Archived from the original on 2022-08-21. Retrieved 2022-08-21.
  11. ↑ Elliott SP (March 2000). "Fatal poisoning with a new phenylethylamine: 4-methylthioamphetamine (4-MTA)". Journal of Analytical Toxicology. 24 (2): 85–89. doi: 10.1093/jat/24.2.85 . PMID   10732944.[ verification needed ]
  12. ↑ De Letter EA, Coopman VA, Cordonnier JA, Piette MH (2001). "One fatal and seven non-fatal cases of 4-methylthioamphetamine (4-MTA) intoxication: clinico-pathological findings". International Journal of Legal Medicine. 114 (6): 352–356. doi:10.1007/s004140100204. PMID   11508803. S2CID   45796753.[ verification needed ]
  13. ↑ Decaestecker T, De Letter E, Clauwaert K, Bouche MP, Lambert W, Van Bocxlaer J, et al. (2001). "Fatal 4-MTA intoxication: development of a liquid chromatographic-tandem mass spectrometric assay for multiple matrices". Journal of Analytical Toxicology. 25 (8): 705–710. doi: 10.1093/jat/25.8.705 . PMID   11765028.[ verification needed ]
  14. ↑ Smets G, Bronselaer K, De Munnynck K, De Feyter K, Van de Voorde W, Sabbe M (August 2005). "Amphetamine toxicity in the emergency department". European Journal of Emergency Medicine. 12 (4): 193–197. doi:10.1097/00063110-200508000-00010. PMID   16034267. S2CID   40206693.[ verification needed ]
  15. ↑ "Report on the Rist Assessment of 4-MTA in the Framework of the Joint Action on New Synthetic Drugs" (PDF). 1999-05-19.
  16. 1 2 Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol. 10: 1590. doi: 10.3389/fphar.2019.01590 . PMC   6989591 . PMID   32038257.
  17. ↑ Błachut D, Wojtasiewicz K, Krawczyk K, Maurin J, Szawkało J, Czarnocki Z (March 2012). "Identification and synthesis of by-products found in 4-methylthioamphetamine (4-MTA) produced by the Leuckart method". Forensic Science International. 216 (1–3): 108–120. doi: 10.1016/j.forsciint.2011.09.005 . PMID   21982394.
  18. 1 2 Ewald AH, Peters FT, Weise M, Maurer HH (September 2005). "Studies on the metabolism and toxicological detection of the designer drug 4-methylthioamphetamine (4-MTA) in human urine using gas chromatography-mass spectrometry". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 824 (1–2): 123–131. doi:10.1016/j.jchromb.2005.07.007. PMID   16027051.
  19. ↑ Carmo H, Hengstler JG, de Boer D, Ringel M, Carvalho F, Fernandes E, et al. (February 2004). "Comparative metabolism of the designer drug 4-methylthioamphetamine by hepatocytes from man, monkey, dog, rabbit, rat and mouse". Naunyn-Schmiedeberg's Archives of Pharmacology. 369 (2): 198–205. doi:10.1007/s00210-003-0850-0. PMID   14676987. S2CID   35836705.
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