Serotonergic neurotoxic thioether metabolites of 3,4- methylenedioxymethamphetamine (MDMA, "ecstasy"): Synthesis, isolation, and characterization of diastereoisomers

Nieves Pizarro, Rafael De La Torre, Jesús Joglar, Noriko Okumura, Ximena Perfetti, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. Catecholthioether metabolites of MDMA, formed via oxidation of 3,4-dihydroxymethamphetamine 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-acetylcystein-S-yl)-HHMA, 2,5-bis-(glutathion-S- yl)-HHMA, and 2,5-bis-(N-acetylcystein-S-yl)-HHMA. Both enzymatic and electrochemical syntheses were explored, and methodologies for analytical and semipreparative 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.

Original languageEnglish (US)
Pages (from-to)2272-2279
Number of pages8
JournalChemical Research in Toxicology
Volume21
Issue number12
DOIs
StatePublished - Dec 15 2008

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N-Methyl-3,4-methylenedioxyamphetamine
Sulfides
Metabolites
Glutathione
Brain
Street Drugs
High Pressure Liquid Chromatography
Nerve Degeneration
Enantiomers
Dialysis Solutions
Neurology
Metabolism
Toxicology
Toxicity
Rats
Animals

ASJC Scopus subject areas

  • Toxicology

Cite this

Serotonergic neurotoxic thioether metabolites of 3,4- methylenedioxymethamphetamine (MDMA, "ecstasy") : Synthesis, isolation, and characterization of diastereoisomers. / Pizarro, Nieves; De La Torre, Rafael; Joglar, Jesús; Okumura, Noriko; Perfetti, Ximena; Lau, Serrine; Monks, Terrence.

In: Chemical Research in Toxicology, Vol. 21, No. 12, 15.12.2008, p. 2272-2279.

Research output: Contribution to journalArticle

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