Synthesis, in vitro formation, and behavioural effects of glutathione regioisomers of alpha-methyldopamine with relevance to MDA and MDMA (ecstasy)

Brain Res. 2003 Oct 17;987(2):144-54. doi: 10.1016/s0006-8993(03)03319-5.


Administration of 3,4-methylenedioxymethamphetamine (MDMA) or 3,4-methylenedioxyamphetamine (MDA) to rats produces serotonergic nerve terminal degeneration. However, they are not neurotoxic when injected directly into the brain, suggesting the requirement for peripheral metabolism of MDMA to a neurotoxic metabolite. Alpha-methyldopamine (alpha-MeDA) is a major metabolite of MDA. There are indications that a glutathione metabolite of alpha-MeDA and/or 3,4-dihydroxymethamphetamine may be responsible for the neurotoxicity and some of the behavioural effects produced by MDMA and/or MDA. The present study details the synthesis, purification and separation of the 5-(glutathion-S-yl)-alpha-MeDA and 6-(glutathion-S-yl)-alpha-MeDA regioisomers of alpha-MeDA. Incubation of MDA with human liver microsomes demonstrated that production of both glutathione adducts are related to cytochrome P450 2D6 isoform activity. Following intracerebroventricular administration (180 nmol) of either GSH adduct into Dark Agouti or Sprague-Dawley rats only 5-(glutathion-S-yl)-alpha-MeDA produced behavioural effects characterised by hyperactivity, teeth chattering, tremor/trembling, head weaving, splayed posture, clonus and wet dog shakes. Pre-treatment with a dopamine receptor antagonist (haloperidol, 0.25 mg/kg; i.p.) attenuated hyperactivity, teeth chattering, low posture and clonus and potentiated splayed postural effects. These results indicate that MDA can be converted into two glutathione regioisomers by human liver microsomes, but only the 5-(glutathion-S-yl)-alpha-MeDA adduct is behaviourally active in the rat.

Publication types

  • Comparative Study

MeSH terms

  • 3,4-Methylenedioxyamphetamine / chemistry
  • 3,4-Methylenedioxyamphetamine / metabolism*
  • 3,4-Methylenedioxyamphetamine / pharmacology
  • Animals
  • Behavior, Animal / drug effects*
  • Behavior, Animal / physiology
  • Cytochrome P-450 CYP2D6 / metabolism
  • Deoxyepinephrine / analogs & derivatives*
  • Deoxyepinephrine / chemistry
  • Deoxyepinephrine / metabolism*
  • Deoxyepinephrine / pharmacology
  • Female
  • Glutathione / chemistry
  • Glutathione / metabolism*
  • Glutathione / pharmacology
  • Humans
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • N-Methyl-3,4-methylenedioxyamphetamine / chemistry
  • N-Methyl-3,4-methylenedioxyamphetamine / metabolism*
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism


  • 3,4-Methylenedioxyamphetamine
  • alpha-methyldopamine
  • Cytochrome P-450 CYP2D6
  • Glutathione
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Deoxyepinephrine