The novel methoxetamine analogs N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK) elicit rapid antidepressant effects via activation of AMPA and 5-HT2 receptors
L. Sayson, Chrislean Jun Botanas, Raly James Perez Custodio, Arvie Abiero, Mikyung Kim, Hyun Jun Lee, H. Kim, Sung Yeun Yoo, Kun Won Lee, Hye Won Ryu, Srijan Acharya, Kyeong-Man Kim, Yong Sup Lee, J. Cheong
Psychopharmacology March 19, 2019 DOI: 10.1007/s00213-019-05219-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | N-ethylnorketamine hydrochloride (NENK) 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK) 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK) |
| Dose | 2.5, 5, and 10 mg/kg |
| Duration | 30 minutes after treatment |
| Topics | 5-MeO-DMT Ketamine Serotonin |
| Key points | Novel MXE analogs induce antidepressant-like effects in mice, likely via AMPA and 5-HT2 receptor activation. |
Abstract
RationaleDepressive syndrome or depression is a debilitating brain disorder affecting numerous people worldwide. Although readily available, current antidepressants have low remission rates and late onset times. Recently, N-methyl-D-aspartate (NMDA) receptor antagonists, like ketamine and methoxetamine (MXE), were found to elicit rapid antidepressant effects. As the search for glutamatergic-based antidepressants is increasing, we synthesized three novel MXE analogs, N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK).ObjectivesTo determine whether the three novel MXE analogs induce antidepressant effects and explore their mechanistic correlation.MethodsWe examined their affinity for NMDA receptors through a radioligand binding assay. Mice were treated with each drug (2.5, 5, and 10 mg/kg), and their behavior was assessed 30 min later in the forced swimming test (FST), tail suspension test (TST), elevated plus-maze (EPM) test, and open-field test (OFT). Another group of mice were pretreated with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin (KS), a 5-HT2 receptor antagonist, during the FST. We also measured mRNA levels of the AMPA receptor subunits GluA1 and GluA2, brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin (mTOR) in the hippocampus and prefrontal cortex.ResultsThe MXE analogs showed affinity to NMDA receptors and decreased immobility time during the FST and TST. NBQX and KS blocked their effects in the FST. The compounds did not induce behavioral alteration during the EPM and OFT. The compounds altered GluA1, GluA2, and BDNF mRNA levels.ConclusionThese results suggest that the novel MXE analogs induce antidepressant effects, which is likely via AMPA and 5-HT2 receptor activation.
Comparable studies
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| Study | Year | Design | Participants |
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| 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
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- R (-)-methoxetamine exerts rapid and sustained antidepressant effects and fewer behavioral side effects relative to S (+)-methoxetamine. Neuropharmacology August 1, 2021
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- New insights into methoxetamine mechanisms of action: Focus on serotonergic 5-HT2 receptors in pharmacological and behavioral effects in the rat. Experimental Neurology November 1, 2021
- Structure identification and analysis of the suspected chemical precursor of 2-fluorodeschloroketamine and its decomposition products. Drug Testing and Analysis June 1, 2022
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