title: Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, Japan. t-hanada@hhc.eisai.co.jp
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hanada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Naoki
authors.initials: N
authors.lastname: Tokuhara
authors.forename: Osamu
authors.initials: O
authors.lastname: Takenaka
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kohmura
authors.forename: Aichi
authors.initials: A
authors.lastname: Ogasawara
authors.forename: Shinji
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohgoh
authors.forename: Masataka
authors.initials: M
authors.lastname: Ueno
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nishizawa
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000032:analysis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D042541:Intracellular Space / Q000737:chemistry; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D011728:Pyridones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; D018091:Receptors, AMPA; C551441:perampanel; D002118:Calcium