Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders
Journal of Medicinal Chemistry – November 20, 2023
Source: OpenAlex
Summary
The prolonged hallucinogenic effects of psilocybin, a potent psychedelic prodrug, often limit its use for anxiety and other psychological conditions. This duration stems from its active metabolite, psilocin. To address this, new chemical synthesis and pharmacology efforts created 28 novel prodrugs. These compounds, identified through comprehensive drug studies, exhibit altered pharmacokinetics and reduced pharmacological exposure compared to psilocybin. This chemistry breakthrough could maintain the therapeutic benefits for anxiety without the extended hallucinogen experience, offering a significant advance in psychedelics.
Abstract
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.