1. Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-d-aspartate receptors.
- Author
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Zhang XL, Li YX, Berglund N, Burgdorf JS, Donello JE, Moskal JR, and Stanton PK
- Subjects
- Humans, HEK293 Cells, Dose-Response Relationship, Drug, Allosteric Regulation drug effects, Allosteric Regulation physiology, Sesterterpenes pharmacology, Animals, Receptors, N-Methyl-D-Aspartate metabolism, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Calcium metabolism
- Abstract
Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca
2+ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca2+ -calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Patric K. Stanton, PhD reports financial support was provided by Gate Neurosciences Inc. Jeffrey S. Burgdorf, PhD reports financial support was provided by Gate Neurosciences Inc. John E. Donello, PhD reports financial support was provided by Gate Neurosciences Inc. Nils Berglund, PhD reports financial support was provided by Gate Neurosciences Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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