Assessment of Bioactivity‐Modulating Pseudo‐Ring Formation in Psilocin and Related Tryptamines
ChemBioChem – April 28, 2022
Source: OpenAlex
Summary
Psilocin, a potent psychedelic tryptamine, profoundly alters consciousness, unlike its close chemical cousin bufotenin. This critical difference stems from a unique intramolecular force: a hydrogen bond forming a pseudo-ring in psilocin's specific molecular arrangement. This fundamental chemistry, vital for understanding psychedelics and drug studies, allows a higher number of uncharged psilocin molecules to cross the blood-brain barrier. Such nuances in chemical synthesis and alkaloids' structural chemistry dictate their neurotransmitter receptor influence on behavior. Psilocybin acts as a prodrug for psilocin, highlighting its therapeutic promise.
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.