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

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 si...

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Bibliographic Details
Published in:ACS chemical neuroscience 2024-06, Vol.15 (12), p.2386-2395
Main Authors: Bryson, Nathan, Alexander, Robert, Asnis-Alibozek, Aviva, Ehlers, Michael D.
Format: Article
Language:English
Subjects:
Animals
Antidepressive Agents - chemical synthesis
Antidepressive Agents - pharmacology
Hallucinogens - chemical synthesis
Hallucinogens - pharmacology
Male
Prodrugs - chemical synthesis
Prodrugs - pharmacology
Rats
Rats, Sprague-Dawley
Tryptamines - chemical synthesis
Tryptamines - chemistry
Tryptamines - pharmacology
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Summary: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.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.4c00058