Assessment of Bioactivity‐Modulating Pseudo‐Ring Formation in Psilocin and Related Tryptamines

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.