Home Products Cited in Publications Worldwide Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders
Raithatha, Sheetal A.; Hagel, Jillian M.; Matinkhoo, Kaveh; Yu, Lisa; Press, David; Cook, Sarah G.; Sharma, Govinda; Dhananjaya, D.; Jensen, Glynnis; Lee, Jessica B.; Cai, Charlie; Gallant, Jonathan; Bains, Jaideep; Tucker, Joseph E.; Facchini, Peter J.
DOI:10.1021/acs.jmedchem.3c01225 PMID:37983270
The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite pos. clin. 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 chem. 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 pharmacol. 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.