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.
Chem Res Toxicol. 2011 Jun 20;24(6):968-78. doi: 10.1021/tx2001459. Epub 2011 May 18.
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.
本研究旨在确定三甲氧苯乙胺（THMA），即 3,4-亚甲二氧基甲基苯丙胺（MDMA，“摇头丸”）的代谢产物，或其硫醚轭合物 6-（N-乙酰半胱氨酸-S-基）-2,4,5-三甲氧苯乙胺（6-NAC-THMA），是否在 MDMA 对脑 5-羟色胺（5-HT）神经元的持久作用中发挥作用。为此，开发了新颖的高产量合成方法来制备 THMA 和 6-NAC-THMA。然后检查了这两种化合物对脑 5-HT 神经元标志物的持久影响。单次脑室注射 THMA 可显著持续耗尽区域大鼠脑 5-HT 和 5-羟吲哚乙酸（5-HIAA），与先前报道的 THMA 具有 5-HT 神经毒性潜力一致。THMA 对脑 5-HT 标志物的持久作用被 5-HT 摄取抑制剂氟西汀阻断，表明 THMA 对 5-HT 标志物的持续作用，就像 MDMA 一样，依赖于完整的 5-HT 转运体功能。试图鉴定在接受高神经毒性剂量（80mg/kg）MDMA 治疗的动物脑中的 THMA，但未成功。未能在这些动物的脑中鉴定出 THMA 与 THMA 分子的不稳定性质无关，因为脑室内给予的外源性 THMA 可以在大鼠脑中持续检测到几个小时。THMA 的硫醚轭合物 6-NAC-THMA 不会导致皮质 5-HT 或 5-HIAA 水平发生可检测的持久改变，表明其缺乏明显的 5-HT 神经毒性活性。目前的结果使人对 THMA 或 6-NAC-THMA 在 MDMA 引起的持久 5-HT 能效应中的作用产生怀疑。THMA 的不同共轭形式或氧化环状形式（例如，THMA 的吲哚）在体内 MDMA 诱导的 5-HT 神经毒性中可能起作用。
