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

## TL;DR

This paper describes new psilocin derivatives designed to reduce hallucinogenic effects while maintaining therapeutic potential for mental health.

## Contribution

The novel fluorinated carbamate derivatives of psilocin allow controlled brain exposure and reduced psychoactivity.

## Key findings

- Fluorinated carbamate derivatives of psilocin showed finely tuned hydrolysis under physiological conditions.
- Lead compound 4e demonstrated oral bioavailability, brain penetration, and partial conversion to psilocin.
- Compound 4e exhibited serotonergic activity but induced 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.