对三胺迷幻药物的结构性见解:基醇环位点在5-HT_2A受体激活和迷幻药类活性中的作用

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Miyuan Zhang¹, Yuefeng Yang¹, Zhishuai Yang²

¹Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, China.

European journal of medicinal chemistry

|November 14, 2024

概括

基团在醇环上的位置显著影响了5-HT_2A受体和迷幻效应中的 псилоцин模拟活性. 与第6位和第7位相比,位于第4位和第5位的基团增强了受体结合和迷幻活性.

科学领域:

神经科学是一个神经科学.
药用化学医学化学
心理药理学心理药理学

背景情况:

衍生的胺类药物,如 псилоцибин和 псилоцин,显示出治疗精神健康状况的治疗潜力.
了解结构-活动关系是开发新疗法的关键.

研究的目的:

为了研究基团在醇环上的位置如何影响5-HT_2A受体活性和类素类似物的迷幻效应.
为了将分子相互作用与观察到的受体活性和行为反应相关联.

主要方法:

化学合成的 псилоцин和类似物 (bufotenine,6-OH-DMT,7-OH-DMT). 化学合成的 псилоцин和类似物 (bufotenine,6-OH-DMT,7-OH-DMT). 化学合成的 псилоцин和类似物 (bufotenine,6-OH-DMT,7-OH-DMT). 化学合成的 псилоцин和类似物.
使用BRET试验评估了5-HT_2A受体的激素活性.
通过头部抽反应试验评估了类似于迷幻的效果.
采用了道元动力学模拟来分析结合的自由能量和分子相互作用.

主要成果:

在第4位和第5位具有基基的类比西洛辛,表现出更高的5-HT_2A激动性和类似于迷幻的活性.
在第6位和第7位基组的化合物表现出明显较低的活动.
分子模拟显示,与L229的结合和与D155的稳定盐桥对强大的5-HT_2AR结合和活性至关重要.

结论:

基团在醇环上的位置是5-HT_2A受体活性和迷幻效应的关键决定因素.
特定的分子相互作用,如键和盐桥,决定了连接体的结合和有效性.
研究结果为设计针对神经和精神疾病的向治疗提供了宝贵的见解.

关键词:

5-HT(2A) 接收器的受体.氧体内醇环的氧体内醇环.分子动力学模拟模型这种药物叫psilocin.类似于迷幻的活动.

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