3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a psychostimulant widely abused among young people. MDMA exhibits distinct pharmacological properties, collectively described as entactogenic, which differentiate it from classic amphetamines (Nichols, 1986). MDMA produces acute and long-term serotonergic neurotoxicity in rodents, primates, and, possibly, in humans, with the severity of toxicity dependent on the dose and frequency of administration (Green et al., 2003). Such neurotoxicity is demonstrated by a decrease in tryptophan hydroxylase activity (Stone et al., 1988), a reduction in serotonin content, a dose-dependent persistent decrease in the number of 5-HT transporter sites and 5-HT receptors in several regions of the brain (Aguirre et al., 1995;Ricaurte et al., 2000), and an impairment of central 5-HT function (Barrionuevo et al., 2000).

No abstract

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a synthetic recreational drug of abuse that produces long-term toxicity associated with the degeneration of serotonergic nerve terminals. In various animal models direct administration of MDMA into the brain fails to reproduce the serotonergic neurotoxicity, implying a requirement for the systemic metabolism and bioactivation of MDMA. Catechol-thioether metabolites of MDMA, formed via oxidation of 3,4-dihydroxymetamphetamine and 3,4-dihydroxyamphetamine (HHMA and HHA) and subsequent conjugation with glutathione (GSH), are selective serotonergic neurotoxicants when administered directly into brain. Moreover, following systemic administration of MDMA, the thioether adducts are present in rat brain dialysate. MDMA contains a stereogenic center, and is consumed as a racemate. Interestingly, different pharmacological properties have been attributed to the two enantiomers, (S)-MDMA being the most active in the central nervous system and responsible for the entactogenic effects, and most likely also for the neurodegeneration. The present study focused on the synthesis and stereochemical analysis of the neurotoxic MDMA thioether metabolites, 5-(glutathion-S-yl)-HHMA, 5-(N-acetylcysteine-S-yl)-HHMA, 2,5-bis-(glutathion-S-yl)-HHMA and 2,5-bis-(N-acetylcysteine-S-yl)-HHMA. Both enzymatic and electrochemical syntheses were explored, and methodologies for analytical and semi-preparative diastereoisomeric separation of MDMA thioether conjugates by HPLC-CEAS and HPLC-UV respectively were developed. Synthesis, diastereoisomeric separation, and unequivocal identification of the thioether conjugates of MDMA provide the chemical tools necessary for appropriate toxicological and metabolic studies on MDMA metabolites contributing to its neurotoxicity.