2. Academic Validation
  3. Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N-Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure

Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N-Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure

  • J Med Chem. 2026 Feb 12;69(3):2145-2159. doi: 10.1021/acs.jmedchem.5c01797.
Marco Banzato 1,  Martina Colognesi 1,  Lorena Lucatello 2,  Stefano Comai 1 3 4,  Gianfranco Pasut 1,  Francesca Capolongo 2,  Laura Orian 5,  Lucia Biasutto 6,  Anna Signor 1,  Daniela Gabbia 1,  Paolo L Manfredi 7,  Sara De Martin 1,  Andrea Mattarei 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Francesco Marzolo 5, Padua 35131, Italy.
  • 2 Department of Comparative Biomedicine and Food Science, University of Padova, Viale dell'Università 16, Legnaro, Padua 35020, Italy.
  • 3 Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, Padua 35131, Italy.
  • 4 Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada.
  • 5 Department of Chemical Sciences, University of Padova, Via Francesco Marzolo 1, Padua 35131, Italy.
  • 6 Italian National Research Council (CNR) Neuroscience Institute, Viale Giuseppe Colombo 3, Padua 35131, Italy.
  • 7 MGGM Therapeutics, 85 Baker Road, Kerhonkson, New York 12446, United States.
PMID: 41586631 DOI: 10.1021/acs.jmedchem.5c01797
Abstract

Psilocybin, the phosphorylated prodrug of psilocin, holds therapeutic promise across a range of neuropsychiatric conditions, yet its clinical utility is constrained by acute psychoactive effects. Here, we report the rational design, synthesis, and evaluation of a focused library of fluorinated reversible N-alkyl carbamate derivatives of psilocin aimed at reducing acute psilocin exposure and thereby limiting hallucinogenic-like effects. Carbamate bond stability was systematically modulated by varying the number and positioning of fluorine atoms on the alkyl promoiety. The resulting compounds exhibited finely tuned hydrolysis under physiological conditions. A selected lead compound (4e) showed favorable oral bioavailability and efficient brain penetration while undergoing partial bioconversion to psilocin. Notably, 4e displayed intrinsic serotonergic activity at 5-HT2A and 5-HT2C receptors but induced attenuated psychotropic effects relative to psilocybin. Overall, these findings highlight fluorinated carbamate chemistry as a versatile platform to control psilocin exposure and serotonergic signaling, rather than the development of a classical pharmacologically inert prodrug.

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