RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 127
OP 133
DO 10.1124/jpet.103.058495
VO 308
IS 1
A1 Hiroshi Yamashita
A1 Kazushige Ohno
A1 Yoko Amada
A1 Hanae Hattori
A1 Yukiko Ozawa-Funatsu
A1 Takashi Toya
A1 Hiroshi Inami
A1 Jun-Ichi Shishikura
A1 Shuichi Sakamoto
A1 Masamichi Okada
A1 Tokio Yamaguchi
YR 2004
UL http://jpet.aspetjournals.org/content/308/1/127.abstract
AB 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