Dizocilpine-derived K2060 exhibits enhanced blockage at NMDA receptors with impaired Mg2+ block and provides strong protection against audiogenic seizures
- 1Institute of Experimental Medicine of the Czech Academy of Sciences, Department of Neurochemistry, Videnska 1083, 142 20 Prague, Czech Republic
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.
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BibTeX
@misc{kolcheva2026dizocilpinederived,
title = {{Dizocilpine-derived K2060 exhibits enhanced blockage at NMDA receptors with impaired Mg2+ block and provides strong protection against audiogenic seizures}},
author = {M. Kolcheva and J. Netolicky and A. Misiachna and N. Rybalko and P. Zahumenska and J. Doderovic and A. Pakhomova and C. V. De Sanctis and G. K. Schneider and K. Hemelikova and K. Rehakova and S. Kortus and R. Turecek and J. Korabecny and O. Soukup and M. Ladislav and M. Horak},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756690},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756690v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Dizocilpine-derived K2060 exhibits enhanced blockage at NMDA receptors with impaired Mg2+ block and provides strong protection against audiogenic seizures
AU - M. Kolcheva
AU - J. Netolicky
AU - A. Misiachna
AU - N. Rybalko
AU - P. Zahumenska
AU - J. Doderovic
AU - A. Pakhomova
AU - C. V. De Sanctis
AU - G. K. Schneider
AU - K. Hemelikova
AU - K. Rehakova
AU - S. Kortus
AU - R. Turecek
AU - J. Korabecny
AU - O. Soukup
AU - M. Ladislav
AU - M. Horak
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756690
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756690v1
AB - 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.
ER -