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.
Highlights
AMPA receptors are members of the ionotropic glutamate receptor family of ligand-gated ion channels [1]
Preapplication of perampanel for 5 s followed by coapplication of perampanel together with AMPA resulted in a reduction in the amplitude of the peak and late AMPA response, where the late response is taken as the current amplitude at the end of the 5 s AMPA perfusion
The results of the present study demonstrate that perampanel is a selective noncompetitive AMPA receptor antagonist
Summary
AMPA receptors are members of the ionotropic glutamate receptor family of ligand-gated ion channels [1]. After the identification of competitive AMPA receptor antagonists, a second type of selective AMPA receptor antagonist was described that acts in a noncompetitive fashion with respect to agonists These negative allosteric modulators include 2,3-benzodiazepines such as GYKI 52466 [6,7,8,9] and the related quinazolinone CP-465,022 [10], which bind within peptide segments of AMPA receptor subunits that link the LBD to the transmembrane spanning region [11]. Antagonist occupancy at this site inhibits the transduction of agonist binding into channel gating
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