title: Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate.
abstract: The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, "ecstasy"), or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), play a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating that persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in the brains of these animals was not related to the unstable nature of the THMA molecule because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA or oxidized cyclic forms (e.g., the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo.
authors.affiliation: UMR 8638 CNRS-Université Paris Descartes, Synthèse et Structure de Molécules d'Intérêt Pharmacologique, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75270 Paris cedex 06, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Neudörffer
authors.forename: Melanie
authors.initials: M
authors.lastname: Mueller
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Martinez
authors.forename: Annis
authors.initials: A
authors.lastname: Mechan
authors.forename: Una
authors.initials: U
authors.lastname: McCann
authors.forename: George A
authors.initials: GA
authors.lastname: Ricaurte
authors.forename: Martine
authors.initials: M
authors.lastname: Largeron
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D009498:Neurotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
chemical_list: C561711:6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine; D018759:Adrenergic Uptake Inhibitors; D009498:Neurotoxins; C074078:2,4,5-trihydroxymethamphetamine; D012701:Serotonin; D008694:Methamphetamine; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D000111:Acetylcysteine