4-Methylamphetamine

4-Methylamphetamine
Ball-and-stick model of the 4-methylamphetamine molecule
Clinical data
Trade namesAptrol
Other names4-MA; PAL-313; PAL313; p-TAP; Normephedrine
Routes of
administration		Oral, intranasal, injection,
Drug classSerotonin-norepinephrine-dopamine releasing agent; Stimulant; Anorectic
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Elimination half-life6–12 hours
ExcretionUrine
Identifiers
  • 1-(4-methylphenyl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC10H15N
Molar mass149.237 g·mol−1
3D model (JSmol)
  • NC(Cc1ccc(cc1)C)C
  • InChI=1S/C10H15N/c1-8-3-5-10(6-4-8)7-9(2)11/h3-6,9H,7,11H2,1-2H3 checkY
  • Key:ZDHZDWSHLNBTEB-UHFFFAOYSA-N checkY
 X markNcheckY (what is this?)  (verify)

4-Methylamphetamine (4-MA) or para-methylamphetamine, also known by the former proposed brand name Aptrol, is a stimulant and anorectic drug of the amphetamine family. It is structurally related to mephedrone (4-methylmethcathinone).

Pharmacology

Pharmacodynamics

In vitro, 4-methylamphetamine acts as a potent and well-balanced serotonin, norepinephrine, and dopamine releasing agent (SNDRA) with EC50Tooltip half-maximal effective concentration values of 53.4 nM, 22.2 nM, and 44.1 nM at the serotonin, norepinephrine, and dopamine transporters, respectively. Receptor interaction data for 4-methylamphetamine have also been reported.

However, more recent in vivo studies that involved performing microdialysis on rats showed a different trend. These studies showed that 4-methylamphetamine is much more potent at elevating serotonin (~18 x baseline) relative to dopamine (~5 x baseline). The authors speculated that this is because 5-HT release dampens DA release through some mechanism. For example, it was suggested that a possible cause for this could be activation of 5HT2C receptors since this is known to inhibit DA release. In addition there are alternative explanations such as 5-HT release then going on to encourage GABA release, which has an inhibitory effect on DA neurons.

In animal studies, 4-MA was shown to have the lowest rate of self-administration out of a range of similar drugs tested (the others being 3-methylamphetamine, 4-fluoroamphetamine, and 3-fluoroamphetamine), likely as a result of having the highest potency for releasing serotonin relative to dopamine.

4-MA produces the head-twitch response in rodents similarly to para-chloroamphetamine (PCA).

Monoamine release of 4-methylamphetamine and related agents (EC50Tooltip Half maximal effective concentration, nM)
CompoundNETooltip NorepinephrineDATooltip Dopamine5-HTTooltip SerotoninRef
Dextroamphetamine6.6–10.25.8–24.8698–1,765
Dextromethamphetamine12.3–14.38.5–40.4736–1,292
4-Methylamphetamine22.244.153.4
4-Methylmethamphetamine (mephedrine)66.941.367.4
4-Methylcathinone (normephedrone)100220210
4-Methylmethcathinone (mephedrone)58–62.749.1–51118.3–122
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs:

Instance of natural occurrence

4-Methylamphetamine occurs naturally as an alkaloid in Thymus quinquecostatus plants, although its content even in young leaves is quite low (3.11 ± 0.05% of the total alkaloid fraction. As the leaves mature, the substance ceases to be detectable.) However, despite the identification of the compound, it is difficult to say whether this study is accurate, given the low level of verifiability and the lack of reliable sources to support the claim.

Society and culture

More than a dozen deaths were reported throughout Europe in 2012-2013 after consumption of amphetamine ('speed') contaminated with 4-methylamphetamine.

Research

4-MA was investigated as an appetite suppressant in 1952 and was even given a trade name, Aptrol, but development was apparently never completed. More recently it has been reported as a novel designer drug.

See also

References

  1. 1 2 3 Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (May 2005). "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics. 313 (2): 848–854. doi:10.1124/jpet.104.080101. PMID 15677348. S2CID 12135483.
  2. ↑ Luethi D, Kolaczynska KE, Docci L, Krähenbühl S, Hoener MC, Liechti ME (May 2018). "Pharmacological profile of mephedrone analogs and related new psychoactive substances". Neuropharmacology. 134 (Pt A): 4–12. doi:10.1016/j.neuropharm.2017.07.026. PMID 28755886.
  3. ↑ Di Giovanni G, Esposito E, Di Matteo V (June 2010). "Role of serotonin in central dopamine dysfunction". CNS Neuroscience & Therapeutics. 16 (3): 179–194. doi:10.1111/j.1755-5949.2010.00135.x. PMC 6493878. PMID 20557570.
  4. ↑ Baumann MH, Clark RD, Woolverton WL, Wee S, Blough BE, Rothman RB (April 2011). "In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat". The Journal of Pharmacology and Experimental Therapeutics. 337 (1): 218–225. doi:10.1124/jpet.110.176271. PMC 3063744. PMID 21228061.
  5. ↑ Ogren SO, Ross SB (October 1977). "Substituted amphetamine derivatives. II. Behavioural effects in mice related to monoaminergic neurones". Acta Pharmacol Toxicol (Copenh). 41 (4): 353–368. doi:10.1111/j.1600-0773.1977.tb02674.x. PMID 303437.
  6. 1 2 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. S2CID 15573624.
  7. 1 2 Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (March 2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC 3572453. PMID 23072836.
  8. 1 2 3 Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W.
  9. 1 2 Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substrates". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID 11680410. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.{{cite book}}: CS1 maint: deprecated archival service (link)
  10. 1 2 Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (April 2012). "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology. 37 (5): 1192–1203. doi:10.1038/npp.2011.304. PMC 3306880. PMID 22169943.
  11. ↑ Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  12. ↑ Solis E, Partilla JS, Sakloth F, Ruchala I, Schwienteck KL, De Felice LJ, et al. (September 2017). "N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability". Neuropsychopharmacology. 42 (10): 1950–1961. doi:10.1038/npp.2017.98. PMC 5561352. PMID 28530234.
  13. ↑ Sakloth F (11 December 2015). Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action. VCU Scholars Compass (Thesis). doi:10.25772/AY8R-PW77.
  14. ↑ Mayer FP, Wimmer L, Dillon-Carter O, Partilla JS, Burchardt NV, Mihovilovic MD, et al. (September 2016). "Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters". Br J Pharmacol. 173 (17): 2657–2668. doi:10.1111/bph.13547. PMC 4978154. PMID 27391165.
  15. ↑ Hutsell BA, Baumann MH, Partilla JS, Banks ML, Vekariya R, Glennon RA, et al. (February 2016). "Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats". Eur Neuropsychopharmacol. 26 (2): 288–297. doi:10.1016/j.euroneuro.2015.12.010. PMC 5331761. PMID 26738428.
  16. ↑ Glennon RA, Dukat M (2017). "Structure-Activity Relationships of Synthetic Cathinones". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. Vol. 32. pp. 19–47. doi:10.1007/7854_2016_41. ISBN 978-3-319-52442-9. PMC 5818155. PMID 27830576.
  17. ↑ Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, et al. (March 2019). "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology. 236 (3): 915–924. doi:10.1007/s00213-018-5063-9. PMC 6475490. PMID 30341459.
  18. ↑ Walther D, Shalabi AR, Baumann MH, Glennon RA (January 2019). "Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents". ACS Chem Neurosci. 10 (1): 740–745. doi:10.1021/acschemneuro.8b00524. PMC 8269283. PMID 30354055.
  19. ↑ Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, et al. (May 2015). "Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues". Br J Pharmacol. 172 (10): 2433–2444. doi:10.1111/bph.13030. PMC 4409897. PMID 25438806.
  20. ↑ Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135.
  21. ↑ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
  22. ↑ Jing H, Liu J, Liu H, Xin H (2014). "Histochemical investigation and kinds of alkaloids in leaves of different developmental stages in Thymus quinquecostatus". TheScientificWorldJournal. 2014 839548. doi:10.1155/2014/839548. PMC 4102088. PMID 25101324.
  23. ↑ Blanckaert P, van Amsterdam J, Brunt T, van den Berg J, Van Durme F, Maudens K, et al. (September 2013). "4-Methyl-amphetamine: a health threat for recreational amphetamine users". Journal of Psychopharmacology. 27 (9): 817–822. doi:10.1177/0269881113487950. PMID 23784740. S2CID 35436194.
  24. ↑ Coppola M, Mondola R (December 2013). "4-methylamphetamine (4-MA): chemistry, pharmacology and toxicology of a new potential recreational drug". Mini Reviews in Medicinal Chemistry. 13 (14): 2097–2101. doi:10.2174/13895575113136660106. PMID 24195663.
  25. ↑ Gelvin EP, McGavack TH (January 1952). "2-Amino-1-(p-methylphenyl)-propane (aptrol) as an anorexigenic agent in weight reduction". New York State Journal of Medicine. 52 (2): 223–226. PMID 14890975.