PDF(Pubmed)
Abstract：
Substituted phenethylamines including 2C (2,5-dimethoxyphenethylamines) and NBOMe (N-(2-methoxybenzyl)phenethylamines) drugs are potent psychoactive substances with little to no knowledge available on their toxicity. In the present in vitro study, we explored the mechanisms underlying the neurotoxicity of six substituted phenethylamines: 2C-T-2, 2C-T-4, 2C-T-7 and their corresponding NBOMes. These drugs were synthesized and chemically characterized, and their cytotoxicity (0-1000 μM) was evaluated in differentiated SH-SY5Y cells and primary rat cortical cultures, by the NR uptake and MTT reduction assays. In differentiated SH-SY5Y cells, mitochondrial membrane potential, intracellular ATP and calcium levels, reactive oxygen species production, and intracellular total glutathione levels were also evaluated. All the tested drugs exhibited concentration-dependent cytotoxic effects towards differentiated SH-SY5Y cells and primary rat cortical cultures. The NBOMe drugs presented higher cytotoxicity than their counterparts, which correlates with the drug\'s lipophilicity. These cytotoxic effects were associated with mitochondrial dysfunction, evident through mitochondrial membrane depolarization and lowered intracellular ATP levels. Intracellular calcium imbalance was observed for 2C-T-7 and 25T7-NBOMe, implying a disrupted calcium regulation. Although reactive species levels remained unchanged, a reduction in intracellular total GSH content was observed. Overall, these findings contribute to a deeper understanding of these drugs, shedding light on the mechanisms underpinning their neurotoxicity.
摘要：
包括2C（2,5-二甲氧基苯乙胺）和NBOMe（N-（2-甲氧基苄基）苯乙胺）在内的取代苯乙胺是有效的精神活性物质，对其毒性知之甚少。在目前的体外研究中，我们探讨了六种取代苯乙胺的神经毒性机制:2C-T-2,2C-T-4,2C-T-7及其相应的NBOMes.这些药物是合成和化学表征的，并在分化的SH-SY5Y细胞和原代大鼠皮质培养物中评估其细胞毒性（0-1000μM），通过NR吸收和MTT减少试验。在分化的SH-SY5Y细胞中，线粒体膜电位，细胞内ATP和钙水平，活性氧的产生，还评估了细胞内总谷胱甘肽水平。所有测试的药物对分化的SH-SY5Y细胞和原代大鼠皮质培养物表现出浓度依赖性细胞毒性作用。NBOMe药物表现出比它们的对应物更高的细胞毒性，这与药物的亲脂性有关。这些细胞毒性作用与线粒体功能障碍有关，通过线粒体膜去极化和降低细胞内ATP水平明显。2C-T-7和25T7-NBOMe细胞内钙失衡，暗示钙调节中断。尽管反应性物种水平保持不变，观察到细胞内总GSH含量降低。总的来说,这些发现有助于更深入地了解这些药物，阐明了支撑其神经毒性的机制。
