诺普西洛辛类似物具有类似于迷幻的活性
Alexander M Sherwood1, Elise K Burkhartzmeyer1, Samuel E Williamson1
1Usona Institute, Madison, Wisconsin 53711, United States.
ACS chemical neuroscience
|January 8, 2024
概括
改变的试胺和西洛辛.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 药用化学 医学化学
背景情况:
- псилоцибин及其代谢物 псилоцин是强大的血清素2A受体 (5-HT2A) 激动剂,具有迷幻效应.
- 诺普西洛辛是一种相关的胺,尽管具有类似的5-HT2A活性,但缺乏迷幻效应,这表明中枢神经系统 (CNS) 的生物可用性发生了变化.
- 假设诺普西洛中的N-甲基组限制了它的中枢神经系统透.
研究的目的:
- 合成诺普西洛辛衍生物与修饰的N-基团来增强脂性和中枢神经系统的透性.
- 评估这些类似物在体内具有类似于迷幻药的效果的结构-活性关系.
- 为了确定对于诺普西洛辛衍生物中枢神经系统中介活性至关重要的结构特征.
主要方法:
- 合成了8种具有多种二次氨基基组的诺普西洛辛类似物.
- 鼠标头部抽反应 (HTR) 试验被用作中枢神经系统介导的迷幻效应的代理.
- 在体外受体结合测试中评估了与血清素受体亚型和其他中枢神经系统点的相互作用.
主要成果:
- N-乙烯类似物 (4-HO-NET) 和N-基,N-基,N-异基和N-基衍生物表现出类似于松素的HTR活性.
- 这些活性类型的有效剂量 (ED50) 从1.1到3.2毫克/公斤不等.
- 较大的N-tert-butyl和N-cyclohexyl组未能产生HTR,这表明了固态限制.
结论:
- 用小的基或基基组修改诺普西洛辛的N-甲基组可以恢复中枢神经系统介导的类似于迷幻的效果.
- 脂友性和N替代物的特定结构特征对脑透和HTR活动至关重要.
- 这些发现提供了对开发新型精神活性胺类药物的结构要求的见解.
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