4-Methylmethamphetamine

Not to be confused with Mephedrone, Meperidine, or Methedrine.
4-Methylmethamphetamine
Clinical data
Other names4-MMA; Mephedrine
Drug classStimulant; Serotonin–norepinephrine–dopamine releasing agent
ATC code
  • None
Legal status
Legal status
Identifiers
  • N-methyl-1-(4-methylphenyl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC11H17N
Molar mass163.264 g·mol−1
3D model (JSmol)
  • c1cc(C)ccc1CC(C)NC
  • InChI=1S/C11H17N/c1-9-4-6-11(7-5-9)8-10(2)12-3/h4-7,10,12H,8H2,1-3H3 checkY
  • Key:GAIWFPOJOHUEBL-UHFFFAOYSA-N checkY
  (verify)

4-Methylmethamphetamine (4-MMA), also known as mephedrine, is a putative stimulant and entactogen drug of the amphetamine family. It acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA).[1][2] The drug is the β-deketo analogue of mephedrone (4-methylmethcathinone; 4-MMC) and the N-methyl analogue of 4-methylamphetamine (4-MA).[3][4]

Pharmacology

Pharmacodynamics

4-MMA acts as a potent and well-balanced serotonin–norepinephrine–dopamine releasing agent (SNDRA).[1][2]

4-MMA induces hyperlocomotion and stereotypy (psychostimulant-like effects) as well as hyperthermia in mice, similarly to methcathinone.[5][6]

In contrast to methamphetamine and methcathinone, 4-MMA appears to produce minimal dopaminergic neurotoxicity in mice.[5][6] Conversely, mephedrone shows no dopaminergic neurotoxicity at all in mice.[5][6] It was theorized that 4-methyl and β-keto substitutions on amphetamines may result in loss of activity at the vesicular monoamine transporter 2 (VMAT2), loss of elevations of cytosolic dopamine concentrations, and consequent loss of dopaminergic neurotoxic potential.[5][6] Accordingly, the dopaminergic neurotoxicity of 4-MMA was greatly enhanced by the dopamine precursor levodopa (L-DOPA), the monoamine oxidase inhibitor (MAOI) pargyline, and methamphetamine (a VMAT2 inhibitor/reverser), all of which are known to increase the cytosolic pool of dopamine.[6] However, in contrast to 4-MMA, the dopaminergic neurotoxicity of methcathinone was enhanced only by levodopa and of mephedrone was enhanced only by methamphetamine.[6]

Monoamine release of 4-methylmethamphetamine and related agents (EC50Tooltip Half maximal effective concentration, nM)
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Ref
Dextroamphetamine 6.6–10.2 5.8–24.8 698–1,765 [7][8][9][10]
Dextromethamphetamine 12.3–14.3 8.5–40.4 736–1,292 [7][11][9][10]
4-Methylamphetamine 22.2 44.1 53.4 [12][13][9]
4-Methylmethamphetamine (mephedrine) 66.9 41.3 67.4 [1][2]
4-Methylethylamphetamine 182 550 102 [1]
4-Methylpropylamphetamine 752 IA 650 [1]
4-Methylbutylamphetamine IA IA IA [1]
4-Methylmethcathinone (mephedrone) 58–62.7 49.1–51 118.3–122 [11][8][14][15][16]
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: [17][18]

See also

References

  1. ^ a b c d e f Solis E, Partilla JS, Sakloth F, Ruchala I, Schwienteck KL, De Felice LJ, Eltit JM, Glennon RA, Negus SS, Baumann MH (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.
  2. ^ a b c Sakloth, Farhana (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.
  3. ^ Meyer MR, Wilhelm J, Peters FT, Maurer HH (March 2010). "Beta-keto amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry". Analytical and Bioanalytical Chemistry. 397 (3): 1225–33. doi:10.1007/s00216-010-3636-5. PMID 20333362. S2CID 21471611.
  4. ^ Coppola M, Mondola R (December 2013). "4-methylamphetamine (4-MA): chemistry, pharmacology and toxicology of a new potential recreational drug". Mini Rev Med Chem. 13 (14): 2097–2101. doi:10.2174/13895575113136660106. PMID 24195663.
  5. ^ a b c d Anneken JH, Angoa-Pérez M, Sati GC, Crich D, Kuhn DM (March 2017). "Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone". J Pharmacol Exp Ther. 360 (3): 417–423. doi:10.1124/jpet.116.237768. PMC 5325074. PMID 28039330.
  6. ^ a b c d e f Anneken JH, Angoa-Perez M, Sati GC, Crich D, Kuhn DM (May 2018). "Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine". Neuropharmacology. 134 (Pt A): 46–56. doi:10.1016/j.neuropharm.2017.08.033. PMC 6083857. PMID 28851615.
  7. ^ a b Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (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.
  8. ^ a b Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (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.
  9. ^ a b c 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.
  10. ^ a b 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.
  11. ^ a b Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV (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.
  12. ^ 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.
  13. ^ Forsyth, Andrea N (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  14. ^ Blough BE, Decker AM, Landavazo A, Namjoshi OA, Partilla JS, Baumann MH, Rothman RB (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.
  15. ^ 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.
  16. ^ Bonano JS, Banks ML, Kolanos R, Sakloth F, Barnier ML, Glennon RA, Cozzi NV, Partilla JS, Baumann MH, Negus SS (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.
  17. ^ 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.
  18. ^ 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.