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

Claudius Lenz, Sebastian Dörner, Felix Trottmann, Christian Hertweck, Dirk Hoffmeister, Alexander M. Sherwood

ChemBioChem April 28, 2022 DOI: 10.1002/cbic.202200183 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Topics Psilocybin
Keywords Tryptamines Prodrug Stereochemistry Intramolecular force Hydrogen bond Ring chemistry
Citations 26
Key findings Psilocin forms an intramolecular hydrogen bond creating a pseudo-ring, which increases the proportion of uncharged species able to cross the blood-brain barrier, unlike its isomer bufotenin.

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.

Comparable studies

Other experimental studies on psilocybin, most cited first.

Study Year Design Participants
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers 1998 Experimental study
Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Participants in controlled laboratory experiments receiving a moderate to high oral... 2015 Validation study using pooled data from five laboratory experiments n = 184
Broadband Cortical Desynchronization Underlies the Human Psychedelic State Healthy human participants 2013 Experimental study
Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer Participants with cancer-related psychiatric distress who completed a parent randomized... 2020 Long-term within-subjects follow-up analysis n = 15
Enzymatic Synthesis of Psilocybin 2017 Laboratory study

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Psilocybin Altered states of consciousness DMT Depression Psychedelic-assisted therapy