Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N -Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure
Journal of Medicinal Chemistry January 26, 2026 Marco Banzato, Martina Colognesi, Lorena Lucatello et al.
A library of fluorinated reversible N-alkyl carbamate derivatives of psilocin was designed and synthesized to reduce acute psilocin exposure and limit hallucinogenic-like effects. By varying the number and positioning of fluorine atoms on the alkyl promoiety, carbamate bond stability was systematically modulated, yielding compounds with finely tuned hydrolysis under physiological conditions. A lead compound (4e) demonstrated favorable oral bioavailability and efficient brain penetration while undergoing partial bioconversion to psilocin. It exhibited intrinsic serotonergic activity at 5-HT2A and 5-HT2C receptors but induced attenuated psychotropic effects compared to psilocybin. Fluorinated carbamate chemistry provides a versatile platform to control psilocin exposure and serotonergic signaling.