RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine
ACS Chemical Neuroscience – May 17, 2024
Source: OpenAlex
Summary
A single 1 mg/kg dose of the novel prodrug RE104 significantly reduced immobility in rats for a week, highlighting its antidepressant potential. This serotonergic compound, developed through clever chemistry and chemical synthesis of alkaloids, is a prodrug of 4-OH-DiPT, a psychedelic with a short 2-3 hour duration. Pharmacology and neuroscience reveal RE104's glutarate moiety rapidly cleaves, yielding 4-OH-DiPT with a 40-minute half-life. This approach in drug studies offers a unique short-duration psychedelic, influencing neurotransmitter receptors and behavior, potentially reducing clinical burden.
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.