Perampanel Inhibition of AMPA Receptor Currents in Cultured Hippocampal Neurons

@article{Chen2014PerampanelIO,
  title={Perampanel Inhibition of AMPA Receptor Currents in Cultured Hippocampal Neurons},
  author={Chao-Yin Chen and Lucas Matt and Johannes W. Hell and Michael A. Rogawski},
  journal={PLoS ONE},
  year={2014},
  volume={9}
}
Perampanel is an aryl substituted 2-pyridone AMPA receptor antagonist that was recently approved as a treatment for epilepsy. The drug potently inhibits AMPA receptor responses but the mode of block has not been characterized. Here the action of perampanel on AMPA receptors was investigated by whole-cell voltage-clamp recording in cultured rat hippocampal neurons. Perampanel caused a slow (τ∼1 s at 3 µM), concentration-dependent inhibition of AMPA receptor currents evoked by AMPA and kainate… Expand
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References

SHOWING 1-10 OF 28 REFERENCES
A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus
TLDR
The concentrations of perampanel required to reduce AMPA receptor-mediated responses are not dissimilar to those in plasma following anti-convulsant doses and are consistent with AMPA receptors antagonism being its primary mode of action. Expand
Selective antagonism of AMPA receptors unmasks kainate receptor-mediated responses in hippocampal neurons
TLDR
A family of new noncompetitive antagonists of AMPA receptors (GYKI 52466 and 53655) minimally affects kainate-induced responses at kainates receptors while completely blocking AMPA receptor-mediated currents, making it possible to separate the responses mediated by each receptor. Expand
GYKI 52466, a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses
TLDR
The results demonstrate the existence of a novel recognition site for an atypical benzodiazepine on non-NMDA receptors and could offer advantages over competitive antagonists in the treatment of glutamate-associated neurological disorders, particularly under conditions in which high levels of the amino acid would render the competitive antagonists relatively ineffective. Expand
Hippocampal neurons exhibit cyclothiazide-sensitive rapidly desensitizing responses to kainate
TLDR
Experiments on hippocampal neurons in which responses to kainate were strongly potentiated by cyclothiazide provide a powerful new tool for analysis of allosteric regulatory mechanisms at AMPA-preferring glutamate receptors. Expand
Functional kainate-selective glutamate receptors in cultured hippocampal neurons.
TLDR
It is found that early after culturing, a high percentage of rat hippocampal neurons express functional, kainate-selective glutamate receptors, which are likely to be native homomeric GluR-6 receptors. Expand
Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist
TLDR
The functional characterization of a novel quinazolin-4-one AMPA receptor antagonist, CP-465,022, is described, which provides a new tool to investigate the role of AMPA receptors in physiological and pathophysiological processes. Expand
AMPA receptors as a molecular target in epilepsy therapy
  • M. Rogawski
  • Chemistry, Medicine
  • Acta neurologica Scandinavica. Supplementum
  • 2013
TLDR
The demonstrated clinical efficacy of perampanel, a high‐potency, orally active non‐competitive AMPA receptor antagonist, supports the concept that AMPA receptors are critical to epileptic synchronization and the generation and spread of epileptic discharges in human epilepsy. Expand
A Point Mutation in the Glutamate Binding Site Blocks Desensitization of AMPA Receptors
TLDR
It is found that replacing the glutamate binding domain S1 of GluR3 with S1 (an AMPA receptor) resulted in a fully active but completely nondesensitizing receptor. Expand
Molecular Mechanism of AMPA Receptor Noncompetitive Antagonism
TLDR
Evidence is provided for substantial conformational changes in the S1-M1 and S2-M4 linkers following agonist binding and channel opening, offering a conceptual frame to account for noncompetitive antagonism of AMPA receptors. Expand
Allosteric regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors by thiocyanate and cyclothiazide at a common modulatory site distinct from that of 2,3-benzodiazepines
TLDR
It is concluded that thiocyanate, a flip-preferring allosteric modulator like cyclothiazide, appears to act by enhancing desensitization at a site that may overlap the site where cyclothsiazide reduces desensItization, whereas 2,3-benzodiazepines act at a distinct site and the block does not involve a modification of desens itization. Expand
...
1
2
3
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