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3,4-Dihydroxymethamphetamine

3,4-Dihydroxymethamphetamine
Clinical data
Other namesHHMA; 3,4-DHMA; Di-OH-MA; α-Methylepinine; α,N-Dimethyldopamine; α-Methyl-N-methyldopamine; 3,4-Dihydroxy-N-methylamphetamine
Identifiers
  • 4-[2-(methylamino)propyl]benzene-1,2-diol
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC10H15NO2
Molar mass181.235 g·mol−1
3D model (JSmol)
  • CC(CC1=CC(=C(C=C1)O)O)NC
  • InChI=1S/C10H15NO2/c1-7(11-2)5-8-3-4-9(12)10(13)6-8/h3-4,6-7,11-13H,5H2,1-2H3
  • Key:NTCPGTZTPGFNOM-UHFFFAOYSA-N

3,4-Dihydroxymethamphetamine (HHMA, 3,4-DHMA), or 3,4-dihydroxy-N-methylamphetamine, also known as α-methylepinine or α,N-dimethyldopamine, is the major metabolite of 3,4-methylenedioxy-N-methylamphetamine (MDMA).[1][2][3] It is formed from MDMA by O-demethylation via cytochrome P450 enzymes including CYP2D6 as well as CYP1A2 and CYP3A4.[1][3]

Along with 3,4-dihydroxyamphetamine (HHA; α-methyldopamine), HHMA may be involved in the serotonergic neurotoxicity of MDMA.[1][4][5][3] However, findings in this regard are conflicting.[3][4][5]

References

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  1. ^ a b c Drevin G, Pena-Martin M, Bauduin A, Baudriller A, Briet M, Abbara C (August 2024). "Pharmacogenomics of 3,4-Methylenedioxymethamphetamine (MDMA): A Narrative Review of the Literature". Pharmaceutics. 16 (8): 1091. doi:10.3390/pharmaceutics16081091. PMC 11359928. PMID 39204437.
  2. ^ Dunlap LE, Andrews AM, Olson DE (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chemical Neuroscience. 9 (10): 2408–2427. doi:10.1021/acschemneuro.8b00155. PMC 6197894. PMID 30001118.
  3. ^ a b c d Aguilar MA, García-Pardo MP, Parrott AC (January 2020). "Of mice and men on MDMA: A translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy')". Brain Research. 1727: 146556. doi:10.1016/j.brainres.2019.146556. PMID 31734398. The metabolites of MDMA are 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), α-methyldopamine (α-MeDA), N-methyl-αmethyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA]. There is a substantial hepatic metabolism of MDMA, since levels of MDA and HMMA exceed that of MDMA in plasma. [...] The metabolites of MDMA, as well as those of DA, enhance the formation of quinoproteins and alter synaptosomal glutathione status, suggesting the role of these metabolites in the neurotoxicity induced by MDMA (Barbosa et al., 2012). However, the major reactive metabolite of MDMA, HHMA, does not contribute to acute or long-term MDMA-induced DA depletion, since peripheral administration of this metabolite fails to alter striatal DA. Furthermore, HHMA has been detected in the brain following its systemic injection, but not after systemic MDMA administration (Escobedo et al., 2005).
  4. ^ a b Seiden LS, Sabol KE (1996). "Methamphetamine and Methylenedioxymethamphetamine Neurotoxicity: Possible Mechanisms of Cell Destruction". In Majewska MD (ed.). Neurotoxicity and Neuropathology Associated with Cocaine Abuse. NIDA research monograph. U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse. pp. 251–276. Retrieved 30 September 2024. Steele and colleagues (1991) found that alpha-methylepinine, a metabolite of MDMA formed by demethylenation, failed to damage the 5-HT system in rats.
  5. ^ a b Schmitt KC, Reith ME (February 2010). "Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse". Annals of the New York Academy of Sciences. 1187: 316–340. doi:10.1111/j.1749-6632.2009.05148.x. PMID 20201860. In humans, MDA and MDMA are largely metabolized via demethylenation by the hepatic CYP2D6 enzyme to the respective 3,4-dihydroxyamphetamine species (α-methyldopamine and α,N-dimethyldopamine).135 In recent years, several investigators have revealed that—much like dopamine—these catechol species readily undergo oxidation to semiquinone and quinone species that can form neurotoxic thioether compounds in vivo.136,137 [...] In particular, the dopaminoquinone-like metabolite of MDA/MDMA can undergo conjugation with the cysteinyl thiol moiety of the endogenous reductant glutathione (GSH) to form the thioether 5-(glutathionyl)-α-methyldopamine (5-(GSH)-αMeDA) or its N-methyl analogue.136 In the central nervous system, the 5-(glutathionyl)-thioethers are ultimately metabolized via the mercapturic acid pathway to form 5-(N-acetyl-cysteinyl)-α-methyldopamine (5-(NAC)-αMeDA) and its N-methyl analogue (5-(NAC)-α,N-diMeDA). The structural formulae of these metabolites and their relative potencies as neurotoxins are displayed in Figure 2. The thioether metabolites are potent serotonergic neurotoxins that can induce a dose-dependent increase in ROS formation and cause caspase-3–mediated apoptosis in cultured cortical neurons.137 Moreover, direct intrastriatal administration of pure 5-(NAC)-α,N-diMeDA in rats fully recapitulates the serotonergic toxicity observed with systemic high-dose MDMA.136 These thioethers are detectable in the rat brain after systemic administration of a high-dose neurotoxic regimen of MDMA—repeated dosing leads to significant accumulation due to a nonlinear increase in elimination half-life.139