Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy.

Abstract

PURPOSE:

To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial-onset seizures.

METHODS:

Perampanel pharmacology was assessed by examining changes in intracellular free Ca(2+) ion concentration ([Ca(2+) ](i) ) in primary rat cortical neurones, and [(3) H]perampanel binding to rat forebrain membranes. Antiseizure activity of orally administered perampanel was examined in amygdala-kindled rats and in mice exhibiting audiogenic, maximal electroshock (MES)-induced, pentylenetetrazole (PTZ) -induced, or 6 Hz-induced seizures.

KEY FINDINGS:

In cultured rat cortical neurones, perampanel inhibited α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced increases in [Ca(2+) ](i) (IC(50) 93 nm vs. 2 μm AMPA). Perampanel had a minimal effect on N-methyl-d-aspartate (NMDA)-induced increases in [Ca(2+) ](i) , and only at a high concentration (30 μm). [(3) H]Perampanel binding to rat forebrain membranes was not significantly displaced by glutamate or AMPA but was displaced by the noncompetitive AMPA receptor antagonists CP465022 (K(i) 11.2 ± 0.8 nm) and GYKI52466 (K(i) 12.4 ± 1 μm). In mice, perampanel showed protective effects against audiogenic, MES-induced, and PTZ-induced seizures (ED(50) s 0.47, 1.6, and 0.94 mg/kg, respectively). Perampanel also inhibited 6 Hz electroshock-induced seizures when administered alone or in combination with other antiepileptic drugs (AEDs). In amygdala-kindled rats, perampanel significantly increased afterdischarge threshold (p<0.05 vs. vehicle), and significantly reduced motor seizure duration, afterdischarge duration, and seizure severity recorded at 50% higher intensity than afterdischarge threshold current (p<0.05 for all measures vs. vehicle). Perampanel caused dose-dependent motor impairment in both mice (TD(50) 1.8 mg/kg) and rats (TD(50) 9.14 mg/kg), as determined by rotarod tests. In mice, the protective index (TD(50) in rotarod test/ED(50) in seizure test) was 1.1, 3.8, and 1.9 for MES-induced, audiogenic, and PTZ-induced seizures, respectively. In rat, dog, and monkey, perampanel had a half-life of 1.67, 5.34, and 7.55 h and bioavailability of 46.1%, 53.5%, and 74.5%, respectively.

SIGNIFICANCE:

These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.

• Authors: Takahisa Hanada, Yutaka Hashizume, Naoki Tokuhara, Osamu Takenaka, Naohiro Kohmura, Aichi Ogasawara, Shinji Hatakeyama, Makoto Ohgoh, Masataka Ueno, Yukio Nishizawa
• Journal: Epilepsia (Epilepsia) Vol. 52 Issue 7 Pg. 1331-40 (Jul 2011) ISSN: 1528-1167 [Electronic] United States
• PMID: 21635236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Chemical References

• Anticonvulsants
• Nitriles
• Pyridones
• Receptors, AMPA
• perampanel
• Calcium

Topics

• Amygdala (drug effects, physiopathology)
• Animals
• Anticonvulsants (therapeutic use)
• Brain (drug effects, metabolism)
• Calcium (analysis)
• Cells, Cultured
• Disease Models, Animal
• Dogs
• Intracellular Space (chemistry)
• Male
• Mice
• Neurons (drug effects, metabolism)
• Nitriles
• Pyridones (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptors, AMPA (antagonists & inhibitors)
• Seizures (drug therapy)