TY - JOUR T1 - Effects of 2-[<em>N</em>-(4-Chlorophenyl)-<em>N</em>-methylamino]-4<em>H</em>-pyrido[3.2-<em>e</em>]-1,3-thiazin-4-one (YM928), an Orally Active α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Antagonist, in Models of Generalized Epileptic Seizure in Mice and Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 127 LP - 133 DO - 10.1124/jpet.103.058495 VL - 308 IS - 1 AU - Hiroshi Yamashita AU - Kazushige Ohno AU - Yoko Amada AU - Hanae Hattori AU - Yukiko Ozawa-Funatsu AU - Takashi Toya AU - Hiroshi Inami AU - Jun-Ichi Shishikura AU - Shuichi Sakamoto AU - Masamichi Okada AU - Tokio Yamaguchi Y1 - 2004/01/01 UR - http://jpet.aspetjournals.org/content/308/1/127.abstract N2 - The anticonvulsant activity of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, was studied in animal models of generalized seizure. YM928 exerted significant anticonvulsant effects in the maximal electroshock (MES) seizure test (ED50 = 7.4 mg/kg p.o.), pentylenetetrazol (PTZ)-induced seizure test (ED50 = 9.6 mg/kg p.o.), AMPA-induced seizure test (ED50 = 5.5 mg/kg p.o.), and strychnine-induced seizure test (ED50 = 14.0 mg/kg p.o.) in mice. Effects in rats were detected in the MES seizure test (ED50 = 4.0 mg/kg p.o.) and PTZ-induced seizure test (ED50 = 6.2 mg/kg p.o.). The profile of YM928 was compared with that of established antiepileptics. Valproate showed beneficial effects in all tests used. In contrast, carbamazepine, phenytoin, lamotrigine, phenobarbital, diazepam, ethosuximide, and gabapentin were not active against seizures induced by at least one stimulant. In the rotarod test, YM928 impaired motor coordination (TD50 = 22.5 mg/kg p.o.). The protective index (TD50 value of the rotarod test/ED50 value of MES seizure) was 3.0, suggesting that YM928 can exert antiepileptic effects with only minor motor disturbances. YM928 at doses of 2, 4, and 8 mg/kg p.o. did not significantly affect the threshold of electroshock seizure in rats after 16 days of repeated administration. These data indicate that YM928 does not induce tolerance after subchronic administration. These results indicate that YM928 is a broad-spectrum anticonvulsant that would prove useful for the treatment of generalized seizure in human epileptic patients. The American Society for Pharmacology and Experimental Therapeutics ER -