The novel non-hallucinogenic compound DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole) induces sedative- and anxiolytic-like activity in mice by a mechanism involving 5-HT2A receptor activation.
Hugo R Arias, Deborah Rudin, Dustin J. Hines, April Contreras, Alican Gulsevin, Dina Manetti, Youssef Anouar, Philippe De Deurwaerdère, Jens Meiler, Maria Novella Romanelli, Matthias E. Liechti, Abdeslam Chagraoui
European Journal of Pharmacology March 5, 2024 DOI: 10.1016/j.ejphar.2024.176329 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | DM506 |
| Dose | 15 mg/kg, 5 mg/kg, 40 mg/kg |
| Topics | Serotonin |
| Keywords | 5-ht2a/2b receptors Anxiolytic activity Ibogaminalog Molecular docking Sedative activity |
| Citations | 12 |
| Key points | DM506 induces dose- and time-dependent anxiolytic- and sedative-like activities in mice through 5-HT2A receptor activation without hallucinogenic effects. |
Abstract
The anxiolytic and sedative-like effects of 3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (DM506), a non-hallucinogenic compound derived from ibogamine, were studied in mice. The behavioral effects were examined using Elevated O-maze and novelty suppressed feeding (NSFT) tests, open field test, and loss of righting reflex (LORR) test. The results showed that 15 mg/kg DM506 induced acute and long-lasting anxiolytic-like activity in naive and stressed/anxious mice, respectively. Repeated administration of 5 mg/kg DM506 did not cause cumulative anxiolytic activity or any side effects. Higher doses of DM506 (40 mg/kg) induced sedative-like activity, which was inhibited by a selective 5-HT2A receptor antagonist, volinanserin. Electroencephalography results showed that 15 mg/kg DM506 fumarate increased the transition from a highly alert state (fast γ wavelength) to a more synchronized deep-sleeping activity (δ wavelength), which is reflected in the sedative/anxiolytic activity in mice but without the head-twitch response observed in hallucinogens. The functional, radioligand binding, and molecular docking results showed that DM506 binds to the agonist sites of human 5-HT2A (Ki = 24 nM) and 5-HT2B (Ki = 16 nM) receptors and activates them with a potency (EC50) of 9 nM and 3 nM, respectively. DM506 was relatively less potent and behaved as a partial agonist (efficacy <80%) for both receptor subtypes compared to the full agonist DOI (2,5-dimethoxy-4-iodoamphetamine). Our study showed for the first time that the non-hallucinogenic compound DM506 induces anxiolytic- and sedative-like activities in naïve and stressed/anxious mice in a dose-, time-, and volinanserin-sensitive manner, likely through mechanisms involving 5-HT2A receptor activation.
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 4
- Non-hallucinogenic compounds derived from iboga alkaloids alleviate neuropathic and visceral pain in mice through a mechanism involving 5-HT2A receptor activation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie June 17, 2024
- Ibogalogs improve spatial and recognition memory in rodents through a mechanism involving 5-HT2A receptor activation-enhanced NMDA receptor activity in hippocampal pyramidal CA1 neurons Biomedicine & Pharmacotherapy November 13, 2025
- Pharmacological characterisation of psilocybin and 5-MeO-DMT discriminative cues in the rat and their translational value for identifying novel psychedelics Journal of Psychopharmacology August 27, 2025
- 5‐HT 2A receptor agonism by tert ‐leucinamide and valinamide synthetic cannabinoids: In vitro and in vivo evidence British Journal of Pharmacology May 5, 2026
Cites 28
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Structure-based discovery of nonhallucinogenic psychedelic analogs Science January 27, 2022
- Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Current Topics in Behavioral Neurosciences 2017
- Lysergic Acid Diethylamide-Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study. Biological Psychiatry February 1, 2023
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