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Psychopharmacology

, Volume 236, Issue 7, pp 2201–2210 | Cite as

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

  • Leandro Val Sayson
  • Chrislean Jun Botanas
  • Raly James Perez Custodio
  • Arvie Abiero
  • Mikyung Kim
  • Hyun Jun Lee
  • Hee Jin Kim
  • Sung Yeun Yoo
  • Kun Won Lee
  • Hye Won Ryu
  • Srijan Acharya
  • Kyeong-Man Kim
  • Yong Sup LeeEmail author
  • Jae Hoon CheongEmail author
Original Investigation

Abstract

Rationale

Depressive 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).

Objectives

To determine whether the three novel MXE analogs induce antidepressant effects and explore their mechanistic correlation.

Methods

We 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.

Results

The 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.

Conclusion

These results suggest that the novel MXE analogs induce antidepressant effects, which is likely via AMPA and 5-HT2 receptor activation.

Keywords

Depressive syndrome NMDA receptor antagonists Methoxetamine analogs AMPA receptors 5-HT2 receptors 

Notes

Acknowledgements

This research was supported by the National Research Foundation (NRF) and funded by the Korean government (2017M3A9G2077568 and 2016R1D1A1B02010387).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Leandro Val Sayson
    • 1
  • Chrislean Jun Botanas
    • 1
  • Raly James Perez Custodio
    • 1
  • Arvie Abiero
    • 1
  • Mikyung Kim
    • 1
  • Hyun Jun Lee
    • 1
  • Hee Jin Kim
    • 1
  • Sung Yeun Yoo
    • 2
  • Kun Won Lee
    • 2
  • Hye Won Ryu
    • 2
  • Srijan Acharya
    • 3
  • Kyeong-Man Kim
    • 3
  • Yong Sup Lee
    • 2
    Email author
  • Jae Hoon Cheong
    • 1
    Email author
  1. 1.Uimyung Research Institute for Neuroscience, Department of PharmacySahmyook UniversitySeoulRepublic of Korea
  2. 2.Medicinal Chemistry Laboratory, Department of Pharmacy & Department of Life and Nanopharmaceutical Sciences, College of PharmacyKyung Hee UniversitySeoulRepublic of Korea
  3. 3.College of PharmacyChonnam National UniversityBuk-guRepublic of Korea

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