Abstract：
Psilocybin (1) is the major alkaloid found in psychedelic mushrooms and acts as a prodrug to psilocin (2, 4-hydroxy-N,N-dimethyltryptamine), a potent psychedelic that exerts remarkable alteration of human consciousness. In contrast, the positional isomer bufotenin (7, 5-hydroxy-N,N-dimethyltryptamine) differs significantly in its reported pharmacology. A series of experiments was designed to explore chemical differences between 2 and 7 and specifically to test the hypothesis that the C-4 hydroxy group of 2 significantly influences the observed physical and chemical properties through pseudo-ring formation via an intramolecular hydrogen bond (IMHB). NMR spectroscopy, accompanied by quantum chemical calculations, was employed to compare hydrogen bond behavior in 4- and 5-hydroxylated tryptamines. The results provide evidence for a pseudo-ring in 2 and that sidechain/hydroxyl interactions in 4-hydroxytryptamines influence their oxidation kinetics. We conclude that the propensity to form IMHBs leads to a higher number of uncharged species that easily cross the blood-brain barrier, compared to 7 and other 5-hydroxytryptamines, which cannot form IMHBs. Our work helps understand a fundamental aspect of the pharmacology of 2 and should support efforts to introduce it (via the prodrug 1) as an urgently needed therapeutic against major depressive disorder.
摘要：
Psilocybin（1）是迷幻蘑菇中发现的主要生物碱，可作为psilocin的前药（2，4-羟基-N，N-二甲基色胺)，一种有效的迷幻剂，对人类意识产生显著的改变。相比之下,位置异构体bufotenin（7，5-羟基-N，N-二甲基色胺）在其报道的药理学上存在显着差异。设计了一系列实验来探索2和7之间的化学差异，特别是测试以下假设：2的C-4羟基通过分子内氢键（IMHB）通过假环形成显着影响观察到的物理和化学性质。核磁共振波谱,伴随着量子化学计算，用于比较4-和5-羟基化色胺中的氢键行为。结果为2中的假环提供了证据，并且4-羟色胺中的侧链/羟基相互作用会影响其氧化动力学。我们得出的结论是，形成IMHBs的倾向会导致更多的不带电物种，这些物种很容易穿过血脑屏障，与7和其他5-羟色胺相比，不能形成IMHBs。我们的工作有助于了解2的药理学的基本方面，并应支持将其引入（通过前药1）作为针对重度抑郁症的迫切需要的治疗方法的努力。
