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

Psilocybin, the main alkaloid in psychedelic mushrooms, acts as a prodrug to psilocin, a potent psychedelic that alters human consciousness. Its positional isomer bufotenin differs in reported pharmacology. Experiments tested whether psilocin's C-4 hydroxy group influences properties through pseudo-ring formation via an intramolecular hydrogen bond (IMHB). NMR spectroscopy and quantum chemical calculations compared hydrogen bond behavior in 4- and 5-hydroxylated tryptamines. Evidence shows a pseudo-ring in psilocin and that sidechain/hydroxyl interactions affect oxidation kinetics. The propensity to form IMHBs leads to more uncharged species that cross the blood-brain barrier, unlike bufotenin. This helps explain psilocin's pharmacology and supports developing psilocybin as a therapy for major depressive disorder.

Study at a glance

Abstract

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.