揭示迷幻 2C 苯乙胺及其 N-苄基苯乙胺 (NBOMe) 类似物的体外毒性特征,Pharmaceuticals

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揭示迷幻 2C 苯乙胺及其 N-苄基苯乙胺 (NBOMe) 类似物的体外毒性特征
Pharmaceuticals ( IF 4.286 ) Pub Date : 2023-08-15 , DOI: 10.3390/ph16081158
Daniel Martins ₁ , Eva Gil-Martins _{1,

2,

3} , Fernando Cagide ₁ , Catarina da Fonseca _{2,

3} , Sofia Benfeito ₁ , Carlos Fernandes ₁ , Daniel Chavarria ₁ , Fernando Remião _{2,

3} , Renata Silva _{2,

3} , Fernanda Borges ₁

Affiliation

麦斯卡林衍生物（2C 苯乙胺）药物通过引入 N-2-甲氧基苄基进行修饰，产生了一系列具有公认的有效致幻作用的新化合物，即 NBOMe 药物。尽管它们在不受监管的药品市场上很普遍，但它们的毒性特征仍然知之甚少，尽管有几份报告强调了急性中毒病例，具有脑和肝毒性。因此，在本研究中，麦司卡林、2C-N（在2C苯乙胺芳环的对位插入硝基）和2C-B（在2C苯乙胺芳环的对位插入溴化物）及其相应的合成了 NBOMe 对应物麦斯卡林-NBOMe、25N-NBOMe 和 25B-NBOMe，并分别在分化的 SH-SY5Y 和 HepG2 细胞系中评估了体外神经和肝细胞毒性。进行了细胞毒性、氧化应激、代谢和能量研究，以评估涉及其毒性的主要途径。我们的结果表明，N-2-甲氧基苄基的存在显着增加了 2C 苯乙胺类药物在两种细胞系中的体外细胞毒性，与同类药物相比，NBOMe 药物的 EC50 值较低。一致地，我们的数据显示药物的亲脂性和 EC50 值之间存在相关性（2C-B 除外）。2C-B 在两种细胞系中均表现出比麦司卡林-NBOMe 更高的细胞毒性作用，这一结果可以用其更高的被动渗透性来解释。所有 NBOMe 衍生物都能穿过血脑屏障。考虑到代谢研究，这些药物的细胞毒性被证明受到细胞色素 P450 (CYP) 抑制的影响，这表明这种酶复合物，特别是 SH-SY5Y 细胞中的 CYP3A4 和 CYP2D6 同工酶，在解毒或生物激活中具有潜在作用。此外，在分化的 SH-SY5Y 细胞中，这些药物能够诱导线粒体膜去极化，并破坏细胞内 GSH 和 ATP 水平，这些效应具有浓度依赖性，并且对于 NBOMe 衍生物更为明显。在测试的实验条件下，任何药物均未检测到 ROS 过量产生。还获得了除 2C-B 之外的两种细胞系中药物亲脂性和 EC50 值之间的相关性。总之，在母体药物中引入 NBOMe 部分显着增加了其亲脂性、脑通透性和细胞毒性作用，同时破坏了 GSH 和 ATP 稳态。CYP3A4 和 CYP2D6 的抑制强调了 CYP 介导的代谢影响这些药物的毒性。

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Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues

Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is still poorly understood, despite several reports highlighting cases of acute intoxication, with brain and liver toxicity. Thus, in this study, mescaline, 2C-N (insertion of a nitro in the para position of the 2C phenethylamines aromatic ring) and 2C-B (insertion of a bromide in the para position of the 2C phenethylamines aromatic ring) and their corresponding NBOMe counterparts, mescaline-NBOMe, 25N-NBOMe and 25B-NBOMe, were synthetized and the in vitro neuro- and hepatocytotoxicity evaluated in differentiated SH-SY5Y and HepG2 cell lines, respectively. Cytotoxicity, oxidative stress, metabolic and energetic studies were performed to evaluate the main pathways involved in their toxicity. Our results demonstrated that the presence of the N-2-methoxybenzyl group significantly increased the in vitro cytotoxicity of 2C phenethylamines drugs in both cell lines, with the NBOMe drugs presenting lower EC50 values when compared to their counterparts. Consistently, our data showed a correlation between the drug’s lipophilicity and the EC50 values, except for 2C-B. The 2C-B presented higher cytotoxic effects in both cell lines than mescaline-NBOMe, a result that can be explained by its higher passive permeability. All the NBOMe derivatives were able to cross the blood–brain barrier. Considering metabolic studies, the cytotoxicity of these drugs was shown to be influenced by inhibition of cytochrome P450 (CYP), which suggests a potential role of this enzyme complex, especially CYP3A4 and CYP2D6 isoenzymes in SH-SY5Y cells, in their detoxification or bioactivation. Furthermore, in differentiated SH-SY5Y cells, the drugs were able to induce mitochondrial membrane depolarization, and to disrupt GSH and ATP intracellular levels, these effects being concentration dependent and more pronounced for the NBOMe derivatives. No ROS overproduction was detected for any of the drugs in the tested experimental conditions. A correlation between a drug’s lipophilicity and the EC50 values in both cell lines, except for 2C-B, was also obtained. In summary, the introduction of a NBOMe moiety to the parent drugs significantly increases their lipophilicity, brain permeability and cytotoxic effects, with GSH and ATP homeostasis disruption. The inhibition of CYP3A4 and CYP2D6 emphasized that CYP-mediated metabolism impacts the toxicity of these drugs.

更新日期：2023-08-15

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