RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine

A prodrug called RE104, which releases the short-acting psychedelic 4-OH-DiPT (structurally similar to psilocin), was characterized in rats. 4-OH-DiPT is a synthetic serotonin 2A receptor agonist with a reported 2-3 hour duration of psychedelic effects, shorter than psilocybin. RE104 incorporates a glutarate moiety that cleaves rapidly in the body to provide the active drug. In rats, plasma concentrations of 4-OH-DiPT correlated with head-twitch intensity, and its half-life was 40 minutes after subcutaneous RE104 administration. A single 1 mg/kg dose of RE104 significantly reduced immobility time in the forced swim test one week later, indicating potential antidepressant activity.

Study at a glance

Abstract

Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.