5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663) Alleviates Dravet Syndrome via Inhibiting Monoamine Oxidase Activity.

Overview

1. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; (K.-S.H.); (Y.S.); (S.S.K.); (D.-S.S.); (J.Y.Y.); (C.H.C.); (G.K.)
2. Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea; (S.H.A.); (D.G.K.); (P.K.); (Y.H.); (S.B.)
3. Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea; (M.N.); (I.-S.J.)
4. Brain Science & Engineering Institute, Kyungpook National University, Daegu 41940, Republic of Korea
5. Department of Medical Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea
6. JD Bioscience Inc., 208 Cheomdan-dwagiro, Buk-gu, Gwangju 61011, Republic of Korea

Abstract

Dravet syndrome (DS) is a severe, catastrophic childhood epilepsy predominantly caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1. In this study, we evaluated the therapeutic potential of 5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663), a novel small molecule designed to address the complex pathophysiology of DS. Using scn1lab knockout (KO) zebrafish larvae—a robust vertebrate model for DS—we demonstrated that GM-90663 significantly alleviates seizure-like behavioral movements and rescues deficit in cognitive-like functions. Whole-cell patch-clamp recordings in hippocampal slices revealed that GM-90663 modulates voltage-gated Na+ channel kinetics; specifically, it suppresses slow ramp-induced currents, thereby effectively attenuating neuronal hyperexcitability. Furthermore, neurochemical profiling indicated that GM-90663 treatment leads to a marked increase in endogenous serotonin (5-HT) levels in both wild-type and KO larvae. Molecular docking simulations and subsequent in vitro enzymatic assays confirmed that this elevation in serotonin is mediated through the potent inhibition of monoamine oxidase (MAO) activity. Collectively, our findings suggest that GM-90663 exerts its anti-seizure effects through a synergistic dual mechanism—stabilizing sodium channel conductance and elevating serotonergic activity—positioning it as a promising multi-target candidate for the treatment of DS.

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Datasets cited

• alphafold.ebi.ac.uk/entry/q6nsn2 — at EMBL-EBI; found in the text, “2.9. Molecular Modeling”

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding authors.

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Version 2, 28 September 2026

• Funding: added National Research Foundation: RS-2024-00411137; Ministry of Trade, Industry and Energy: RS-2024-00449703; Korea Research Institute of Chemical Technology: KK2631-20; National Research Foundation of Korea: RS‐2024‐00411137, RS-2024-00348338; National Research Council of Science and Technology: KK2631-20, RS-2024-00411137; Ministry of Science and ICT, South Korea: RS-2024-00348338, RS-2024-00411137

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 17 authors, 5 keywords, 11 MeSH terms, 44 references.

Cite

This paper

Hwang, K.-S., Ahn, S. H., Son, Y., Kim, S. S., Shin, D.-S., Yang, J. Y., Chae, C. H., Nakamura, M., Jang, I.-S., Kim, G., Kim, D. G., Kim, P., Heo, Y., Bae, S., Lee, H., Ahn, J. H., & Bae, M. A. (2026). 5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663) Alleviates Dravet Syndrome via Inhibiting Monoamine Oxidase Activity. Molecules (Basel, Switzerland), 31(9), 1511. https://doi.org/10.3390/molecules31091511

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