Synthesis and Neurotoxicity Profile of 2,4,5-Trihydroxymethamphetamine and Its 6-( N -Acetylcystein- S -yl) Conjugate

Anne Neudörffer , Melanie Mueller , Claire-Marie Martinez , Annis Mechan , Una Mccann , George Ricaurte , Martine Largeron (1)

1 CiTCoM - UMR 8038 - Cibles Thérapeutiques et conception de médicaments

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), plays 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 5hydroxyindoleacetic 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 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 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.

Domaines: Chimie; Chimie théorique et/ou physique; Chimie organique; Sciences du Vivant [q-bio]; Toxicologie; Neurosciences [q-bio.NC]

Anne Neudörffer, Melanie Mueller, Claire-Marie Martinez, Annis Mechan, Una Mccann, et al.. Synthesis and Neurotoxicity Profile of 2,4,5-Trihydroxymethamphetamine and Its 6-( N -Acetylcystein- S -yl) Conjugate. Chemical Research in Toxicology, 2011, 24 (6), pp.968-978. ⟨10.1021/tx2001459⟩. ⟨hal-02384825⟩