RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine
Nathan Bryson, Robert Alexander, Aviva Asnis-Alibozek, Michael Ehlers
ACS Chemical Neuroscience May 17, 2024 DOI: 10.1021/acschemneuro.4c00058 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Randomized Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | RE104 |
| Dose | 1 mg/kg |
| Duration | 1 week |
| Topics | Serotonin |
| Keywords | Prodrug Pharmacology Stereochemistry |
| Citations | 9 |
| Key points | The glutarate ester prodrug RE104 efficiently delivers the short-duration psychedelic 4-OH-DiPT, which shows translational antidepressant potential in rats. |
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 7
- The ABCs of psychedelics: a preclinical roadmap for drug discovery. TIPS - Trends in Pharmacological Sciences August 28, 2025
- Modification of natural tryptamines for the treatment of neuropsychiatric diseases Journal of Psychopharmacology October 4, 2025
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RE104: A Double-Blind, Randomized, Single Ascending Dose Placebo-Controlled Study. Journal of Clinical Psychopharmacology July 21, 2025
- Exploring Psychedelics for Unmet Needs in Women's Reproductive Health. Psychedelic Medicine June 1, 2025
- Towards "unmakable" psychedelics: SAR exploration of psilocin analogs obtained by a HATU-mediated amide coupling strategy European Journal of Medicinal Chemistry Reports June 3, 2025
and 2 more in the library
Cites 23
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
and 18 more in the library