Alberto-Silva Ana Sofia, Hemmer Selina, Bock Hailey A, Alves da Silva Leticia, Scott Kenneth R, Kastner Nina, Bhatt Manan, Niello Marco, Jäntsch Kathrin, Kudlacek Oliver, Bossi Elena, Stockner Thomas, Meyer Markus R, McCorvy John D, Brandt Simon D, Kavanagh Pierce, Sitte Harald H
bioRxiv. 2024 Apr 11:2024.04.08.588083. doi: 10.1101/2024.04.08.588083.
3,4-Methylenedioxymethamphetamine (MDMA, ' ) is re-emerging in clinical settings as a candidate for the treatment of specific psychiatric 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. methods included radiotracer assays, transporter electrophysiology, bioluminescence resonance energy transfer and fluorescence-based assays, pooled human liver microsome/S9 fraction incubation with isozyme mapping, and liquid chromatography coupled to high-resolution mass spectrometry. methods included molecular docking. Compared with MDMA, all three MDMA bioisosteres (ODMA, TDMA, and SeDMA) showed similar pharmacological activity at human serotonin and dopamine transporters (hSERT and hDAT, respectively) but decreased activity at 5-HT receptors. Regarding their hepatic metabolism, they differed from MDMA, with -demethylation being the only metabolic route shared, and without forming phase II metabolites. Additional screening for their interaction with human organic cation transporters (hOCTs) and plasma membrane transporter (hPMAT) revealed a weaker interaction of the MDMA analogs with hOCT1, hOCT2, and hPMAT. Our findings suggest that these new MDMA analogs might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT and hDAT, but displaying a reduced activity at 5-HT receptors and reduced hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.
3,4-亚甲基二氧甲基苯丙胺（摇头丸，MDMA）作为一种与心理治疗相结合用于治疗特定精神疾病（如创伤后应激障碍）的候选药物，正在重新出现在临床环境中。MDMA是一种精神活性药物，通常被视为共情剂或促触觉剂，它会导致转运体介导的单胺释放。尽管MDMA具有治疗潜力，但在安全环境之外，它会引发剂量、个体和环境依赖性的不良影响。在本研究中，我们调查了MDMA的三种新的亚甲二氧基生物电子等排体是否能改善其脱靶特性。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基于荧光的测定、人肝微粒体/ S9组分与同工酶图谱的混合孵育，以及液相色谱与高分辨率质谱联用。方法包括分子对接。与MDMA相比，所有三种MDMA生物电子等排体（ODMA、TDMA和SeDMA）在人血清素和多巴胺转运体（分别为hSERT和hDAT）上表现出相似的药理活性，但在5-HT受体上的活性降低。关于它们的肝脏代谢，它们与MDMA不同，仅有的共同代谢途径是N -去甲基化，且不形成II相代谢物。对它们与人有机阳离子转运体（hOCTs）和质膜转运体（hPMAT）相互作用的额外筛选显示，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类似物可能构成有吸引力的MDMA治疗替代物，保留了在hSERT和hDAT上的主要药理活性，但在5-HT受体上的活性降低且肝脏代谢减少。这些MDMA生物电子等排体是否可能为临床重新出现的MDMA带来风险更低的替代物，还有待进一步研究。
