ucb L059, a novel anti-convulsant drug: pharmacological profile in animals.
The anticonvulsant activity of ucb L059 ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) was evaluated in a range of animal models. ucb L059 was active after oral and intraperitoneal administration in both rats and mice, with a unique profile of action incorporating features in common with several different types of antiepileptic drugs. The compound was active, with ED50 values generally within the range of 5.0-30.0 mg/kg, in inhibiting audiogenic seizures, electrically induced convulsions and convulsions induced chemically by pentylenetetrazole (PTZ), bicuculline, picrotoxin and N-methyl-D-aspartate (NMDA). ucb L059 retarded the development of PTZ-induced kindling in mice and reduced PTZ-induced EEG spike wave discharge in rats. The R enantiomer, ucb L060, had low intrinsic anticonvulsant activity, showing the stereospecificity of action of the molecule although the actual mechanism of action remains unknown. Neurotoxicity, evaluated with an Irwin-type observation test, the rotarod test and open-field exploration, was minimal, with only mild sedation being observed, even at doses 50-100 times higher than the anticonvulsant doses; at pharmacologically active doses, the animals appeared calm but slightly more active. ucb L059 thus presents as an orally active, safe, broad-spectrum anticonvulsant agent, with potential antiepileptogenic and anti-absence actions.
Gower
A J
AJ
UCB Pharmaceutical Sector, Chemin du Foriest, Braine l'Alleud, Belgium.
Noyer
M
M
Verloes
R
R
Gobert
J
J
Wülfert
E
E
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D003292:Convulsants / Q000037:antagonists & inhibitors* / Q000633:toxicity; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects; D000077287:Levetiracetam; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D010889:Piracetam / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D000927:Anticonvulsants; D003292:Convulsants; D000077287:Levetiracetam; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D010889:Piracetam