4-Methylamphetamine

Last updated

4-Methylamphetamine
4-Methylamphetamine.svg
4-Methylamphetamine molecule ball.png
Clinical data
Trade names Aptrol
Other names4-MA; PAL-313; PAL313; p-TAP; Normephedrine
Routes of
administration 		Oral, intranasal, injection,
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 6–12 hours
Excretion Urine
Identifiers
  • 1-(4-methylphenyl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C10H15N
Molar mass 149.237 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 Yes check.svgY
  • Key:ZDHZDWSHLNBTEB-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

4-Methylamphetamine (4-MA), 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).

Contents

Pharmacology

In vitro , 4-methylamphetamine acts as a potent and well-balanced serotonin, norepinephrine, and dopamine releasing agent (SNDRA) with EC50 Tooltip half-maximal effective concentration values of 53.4 nM, 22.2 nM, and 44.1 nM at the serotonin, norepinephrine, and dopamine transporters, respectively. [1]

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. [2]

Monoamine release of 4-methylamphetamine and related agents (EC50 Tooltip Half maximal effective concentration, nM)
Compound NE Tooltip Norepinephrine DA Tooltip Dopamine 5-HT Tooltip SerotoninRef
Dextroamphetamine 6.6–10.25.8–24.8698–1,765 [3] [4] [5] [6]
Dextromethamphetamine 12.3–14.38.5–40.4736–1,292 [3] [7] [5] [6]
4-Methylamphetamine 22.244.153.4 [8] [9] [5]
4-Methylmethamphetamine (mephedrine)66.941.367.4 [10] [11]
4-Methylcathinone (normephedrone)100220210 [12] [13] [14]
4-Methylmethcathinone (mephedrone)58–62.749.1–51118.3–122 [7] [4] [15] [16] [17]
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: [18] [19]

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. [20] More recently it has been reported as a novel designer drug.

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. [1] [21]

Society and culture

More than a dozen deaths were reported throughout Europe in 2012-2013 after consumption of amphetamine ('speed') contaminated with 4-methylamphetamine. [22] [23] [24]

See also

References

  1. 1 2 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. ↑ 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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 Substractes". 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.
  7. 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.
  8. ↑ 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.
  9. ↑ Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  10. ↑ 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.
  11. ↑ 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 . Retrieved 24 November 2024.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.{{cite book}}: |journal= ignored (help)
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ "4-Methyl-amphetamine: A health threat for recreational amphetamine users". ResearchGate.
  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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.