Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT_2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT_2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activity.

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动态模拟迷幻色胺的膜渗透

对迷幻化合物重新产生的科学兴趣是解决当前精神健康障碍负担的最有希望的途径之一。经典致幻剂是一组与天然神经递质血清素 (5-HT) 结构相似的化合物。致幻剂作用于 5-HT 2A 型受体 (HT _2A Rs)，可诱导持久的神经生理变化，与其治疗心理和行为效果相平行。最近的临床前证据表明，致幻剂发挥作用的能力取决于其渗透神经元膜靶向细胞内 5-HT _2A R 库的能力。在这项计算研究中，我们采用经典的分子动力学模拟和伞式采样技术来研究 12 种选定的色胺的渗透行为，并表征驱动该过程的相互作用。我们的目标是阐明 N-烷基化、吲哚环取代和位置修饰以及质子化对其膜渗透性的影响。伯胺基的二甲基化和在5位引入甲氧基表现出渗透性的增加。此外，位置取代对吲哚基团有显着影响，分子的质子化大大增加了双层中心的能垒，使化合物具有高度的不可渗透性。从模拟预测的趋势中提取的所有信息都可以应用于未来的药物设计项目，以开发具有增强活性的迷幻药。