{
  "abstract": "Background and Purpose: Voltage-dependent Mg2+ block is a defining feature of the GluN1/GluN2 subtype of N-methyl-D-aspartate receptors (NMDARs). We tested how impaired Mg2+ block at GluN1/GluN2A receptors mutated at the GluN2A-N615 position modifies inhibition by dizocilpine-derived K2060 compared with clinically used memantine and ketamine. Experimental Approach: Electrophysiological recordings were performed on recombinant wild-type (WT) and mutated GluN1/GluN2A receptors expressed in HEK293T cells. Acute hippocampal slice electrophysiology and behavioural studies were conducted in WT and knock-in GluN2A-N615S mice. In vivo tolerability and efficacy were evaluated using open field testing, prepulse inhibition (PPI), and protection against audiogenic seizures (AGS). Key Results: Mg2+ reduced the apparent potency of all three blockers and slowed onset at the GluN1/GluN2A-WT receptor. These Mg2+-dependent effects were absent or markedly reduced at the GluN1/GluN2A-N615S and GluN1/GluN2A-N615K receptors. In addition, K2060 showed slower unbinding and greater trapping than memantine. In hippocampal slices from GluN2A-N615S mice, K2060 exhibited enhanced but slower onset inhibition than memantine and ketamine. In vivo, K2060 caused no overt behavioural disruption at 5 mg/kg (i.p.) and did not further disrupt PPI. All three blockers protected GluN2A-N615S mice against AGS at 5 mg/kg (i.p.); only K2060 remained protective at 1 mg/kg (i.p.). Conclusions and Implications: Impaired Mg2+; block removes a physiological constraint on the action of NMDAR blockers. K2060 exhibited the most favourable pharmacological profile, supporting its further evaluation for studies with NMDAR hyperfunction models. Additional pharmacokinetic, safety, and disease-model studies are warranted.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Experimental Medicine of the Czech Academy of Sciences, Department of Neurochemistry, Videnska 1083, 142 20 Prague, Czech Republic"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "M. Kolcheva"
    },
    {
      "name": "J. Netolicky"
    },
    {
      "name": "A. Misiachna"
    },
    {
      "name": "N. Rybalko"
    },
    {
      "name": "P. Zahumenska"
    },
    {
      "name": "J. Doderovic"
    },
    {
      "name": "A. Pakhomova"
    },
    {
      "name": "C. V. De Sanctis"
    },
    {
      "name": "G. K. Schneider"
    },
    {
      "name": "K. Hemelikova"
    },
    {
      "name": "K. Rehakova"
    },
    {
      "name": "S. Kortus"
    },
    {
      "name": "R. Turecek"
    },
    {
      "name": "J. Korabecny"
    },
    {
      "name": "O. Soukup"
    },
    {
      "name": "M. Ladislav"
    },
    {
      "affs": [
        0
      ],
      "name": "M. Horak"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5v8wak53ar1wd.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.06.756690",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756690v1.full",
  "id": "5v8wak53ar1wd",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756690v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2804|Neuroscience and Neuropharmacology Research"
    ]
  ],
  "openalex": "W7221716729",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756690v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5v8wak53ar1wd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:27:33Z",
      "native_id": "10.64898/2026.10.06.756690",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756690v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Dizocilpine-derived K2060 exhibits enhanced blockage at NMDA receptors with impaired Mg2+ block and provides strong protection against audiogenic seizures",
  "title_text": "Dizocilpine-derived K2060 exhibits enhanced blockage at NMDA receptors with impaired Mg2+ block and provides strong protection against audiogenic seizures",
  "type": "preprint",
  "updated_at": "2026-10-30T12:27:33Z",
  "url": "https://research.draconitic.com/paper/5v8wak53ar1wd",
  "venue": "bioRxiv",
  "versions": []
}