title: Perampanel inhibition of AMPA receptor currents in cultured hippocampal neurons.
abstract: 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. The rates of block and unblock of AMPA receptor currents were 1.5×105 M-1 s-1 and 0.58 s-1, respectively. Perampanel did not affect NMDA receptor currents. The extent of block of non-desensitizing kainate-evoked currents (IC50, 0.56 µM) was similar at all kainate concentrations (3-100 µM), demonstrating a noncompetitive blocking action. Parampanel did not alter the trajectory of AMPA evoked currents indicating that it does not influence AMPA receptor desensitization. Perampanel is a selective negative allosteric AMPA receptor antagonist of high-affinity and slow blocking kinetics.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Chao-Yin
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Lucas
authors.initials: L
authors.lastname: Matt
authors.affiliation: Department of Pharmacology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Johannes Wilhelm
authors.initials: JW
authors.lastname: Hell
authors.affiliation: Department of Neurology, School of Medicine and Center for Neuroscience, University of California Davis, Sacramento, California, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rogawski
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology*; D007608:Kainic Acid / Q000494:pharmacology; D007700:Kinetics; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D009570:Nitriles; D011247:Pregnancy; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D009570:Nitriles; D011728:Pyridones; D018091:Receptors, AMPA; C551441:perampanel; D007608:Kainic Acid