[Biomimetic electrochemical synthesis of quinol-thioether conjugates: their implication in the serotonergic neurotoxicity of amphetamine derivatives].
Injection of 3,4-methylenedioxyamphetamine (MDA) or 3,4-methylenedioxymethylamphetamine (MDMA or ecstasy) directly into the brain fails to reproduce the long-term effects observed after peripheral administration, implying an essential role for systemic metabolites in the development of toxicity. However, the precise identity of the metabolites participating in MDA and MDMA-mediated serotonergic neurotoxicity remains unclear: neither 3,4-alpha-methyldopamine, nor N-methyl-alpha-methyldopamine, major metabolites, produce neurotoxicity following peripheral administration. In vivo, these metabolites are oxidized to the corresponding orthoquinones, that readily react with protein and nonprotein sulphydryls including glutathione (GSH). The resulting quinol-thioether conjugates exhibit a variety of toxicological activities, which can be regulated by intramolecular cyclisation reactions that occur subsequent to oxidation. The ability of quinol-thioether conjugates to redox cycle and produce reactive oxygen species provides a rationale for the potential role of these metabolites in MDA and MDMA neurotoxicity. A biomimetic  one-pot  synthesis of 5-(GSH-S-yl)-N-Me-alpha-Me-DA involving addition of GSH to the electrogenerated orthoquinone species, is reported to evaluate its in vivo potential neurotoxicity.
Largeron
M
M
Laboratoire de Chimie analytique et Electrochimie, Faculté des Sciences pharmaceutiques et biologiques, Université Paris 5, 4, avenue de l'Observatoire, F 75270 Paris Cedex 06.
Neudorffer
A
A
Gramond
J P
JP
Fleury
M B
MB
D000662:Amphetamines / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D004563:Electrochemistry; D006213:Hallucinogens / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000633:toxicity; D018716:Molecular Mimicry; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000493:pharmacokinetics / Q000633:toxicity; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D012701:Serotonin / Q000502:physiology*; D013440:Sulfides / Q000138:chemical synthesis* / Q000633:toxicity
D000662:Amphetamines; D006213:Hallucinogens; D006873:Hydroquinones; D013440:Sulfides; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine
Synthèse électrochimique biomimétique de conjugués quinol-thioéthers: leur implication dans la neurotoxicité sérotoninergique de dérivés de l'amphétamine.