Synthesis and cyclic voltammetry studies of 3,4-methylenedioxymethamphetamine (MDMA) human metabolites

3.4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a widely abused, psychoactive recreational drug. There are growing evidences that the MDMA neurotoxic profile may be highly dependent on its hepatic metabolism. MDMA metabolism leads to the production of highly reactive derivates, namely catechols, catechol thioethers, and quinones. In this study the electrochemical oxidation-reduction processes of MDMA human metabolites, obtained by chemical synthesis, were evaluated by cyclic voltammetry based on an electrochemical cell with a glassy carbon working electrode. The toxicity of alpha-methyldopamine (alpha-MeDA), N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and 5-(glutathion-S-yl)-alpha-methyldopamine [5-(GSH)-alpha-MeDA] to rat cortical neurons was then correlated with their redox potential. The obtained data demonstrated that the lower oxidation potential observed for the catecholic thioether of alpha-MeDA correlated with the higher toxicity of this adduct. This accounts for the use of voltammetry data in predicting the toxicity of MDMA metabolites.