Abstract

Psilocin and related 5-HT receptor agonists have recently gained attention as potential therapeutics for the treatment of depression and other psychiatric disorders. As psilocin lacks chemical stability, it is traditionally administered as its highly polar prodrug psilocybin. Oral, fixed-dose administration of psilocybin entails treatment sessions of several hours and does not take inter-individual variability of pharmacokinetic and subjective effects into account. Intravenous injection, on the other hand, is less compatible with the treatment setting. In order to optimize the treatment with psilocin in clinical practice, the development of psilocin prodrugs with altered pharmacokinetic profiles, compared to psilocybin, is desirable.

To this end, we have designed, synthesized, and pharmacologically characterized prodrugs of psilocin and related 4-hydroxytryptamines which were formerly unknown or required wasteful and cumbersome synthetic procedures. In the course of our studies, we devised a synthetic route which provides facile access to this prodrug class and prepared several representatives. The high passive membrane permeability of the obtained compounds renders them suitable for non-invasive formulations that circumvent the gastrointestinal tract. Moreover, structural variation of the prodrugs permits a systematic modulation of their key properties, in particular the drug release rate in human plasma and chemical stability.

Further investigation of this promising prodrug class is ongoing as several benefits for therapeutic treatments may be envisioned.