Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders

The psychedelic prodrug
psilocybin has shown therapeutic benefits
for the treatment of numerous psychiatric conditions. Despite positive
clinical end points targeting depression and anxiety, concerns regarding
the duration of the psychedelic experience produced by psilocybin,
associated with enduring systemic exposure to the active metabolite
psilocin, pose a barrier to its therapeutic application. Our objective
was to create a novel prodrug of psilocin with similar therapeutic
benefits but a reduced duration of psychedelic effects compared with
psilocybin. Here, we report the synthesis and functional screening
of 28 new chemical entities. Our strategy was to introduce a diversity
of cleavable groups at the 4-hydroxy position of the core indole moiety
to modulate metabolic processing. We identified several novel prodrugs
of psilocin with altered pharmacokinetic profiles and reduced pharmacological
exposure compared with psilocybin. These candidate prodrugs have the
potential to maintain the long-term benefits of psilocybin therapy
while attenuating the duration of psychedelic effects.