Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany.
J Neurochem. 2024 Sep;168(9):2022-2042. doi: 10.1111/jnc.16149. Epub 2024 Jun 19.
3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is re-emerging in clinical settings as a candidate for the treatment of specific neuropsychiatric disorders (e.g. post-traumatic stress disorder) in combination with psychotherapy. MDMA is a psychoactive drug, typically regarded as an empathogen or entactogen, which leads to transporter-mediated monoamine release. Despite its therapeutic potential, MDMA can induce dose-, individual-, and context-dependent untoward effects outside safe settings. In this study, we investigated whether three new methylenedioxy bioisosteres of MDMA improve its off-target profile. In vitro methods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence-based assays, pooled human liver microsome/S9 fraction incubations, metabolic stability studies, isozyme mapping, and liquid chromatography coupled to high-resolution mass spectrometry. In silico methods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin, dopamine, and norepinephrine transporters (hSERT, hDAT, and hNET, respectively) but decreased agonist activity at 5-HT receptors. Regarding their hepatic metabolism, they differed from MDMA, with N-demethylation being the only metabolic route shared, and without forming phase II metabolites. In addition, TDMA showed an enhanced intrinsic clearance in comparison to its congeners. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane monoamine transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5-HT receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.
3,4-亚甲二氧基甲基苯丙胺（MDMA，“摇头丸”）作为一种治疗特定神经精神疾病（如创伤后应激障碍）的候选药物，与心理治疗相结合，在临床环境中重新出现。MDMA 是一种精神活性药物，通常被认为是一种移情剂或交互剂，可导致转运体介导的单胺释放。尽管具有治疗潜力，但 MDMA 在安全环境之外会引起剂量、个体和环境相关的不良影响。在这项研究中，我们研究了三种新的亚甲二氧基 MDMA 生物等排物是否能改善其非靶标特征。体外方法包括放射性示踪剂测定、转运体电生理学、生物发光共振能量转移和荧光测定、混合人肝微粒体/S9 级分孵育、代谢稳定性研究、同工酶图谱和液相色谱-高分辨率质谱联用。在计算方法中包括分子对接。与 MDMA 相比，所有三种 MDMA 生物等排物（ODMA、TDMA 和 SeDMA）在人 5-羟色胺、多巴胺和去甲肾上腺素转运体（hSERT、hDAT 和 hNET）上均表现出相似的药理学活性，但在 5-HT 受体上的激动活性降低。关于它们的肝代谢，它们与 MDMA 不同，只有 N-去甲基化是唯一的代谢途径，没有形成相 II 代谢物。此外，TDMA 的内在清除率比其同系物增强。进一步筛选它们与人类有机阳离子转运体（hOCTs）和质膜单胺转运体（hPMAT）的相互作用表明，MDMA 类似物与 hOCT1、hOCT2 和 hPMAT 的相互作用较弱。我们的研究结果表明，这些新的 MDMA 生物等排物可能构成 MDMA 的有吸引力的治疗替代物，保留 hSERT、hDAT 和 hNET 的主要药理学活性，但在 5-HT 受体和替代肝代谢方面活性降低。这些 MDMA 生物等排物是否可能成为临床重新出现的 MDMA 的较低风险替代品，需要进一步研究。
