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
Source: OpenAlex
Summary
A novel approach significantly reduces the hallucinogenic effects of psilocybin, a promising psychedelic for neuropsychiatric conditions. Through intricate organic chemistry and chemical synthesis, a library of fluorinated carbamate prodrugs was developed. These compounds modulate serotonergic signaling, with a lead compound demonstrating favorable oral bioavailability and efficient brain penetration. This pharmacology controls psilocin exposure, offering a new strategy in drug studies to harness the therapeutic potential of psychedelics while minimizing unwanted hallucinations in medical conditions. Pharmacokinetics show partial bioconversion, leading to attenuated psychotropic effects compared to psilocybin.
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.