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NEUROPHARMACOLOGY

Effects of 2-[N-(4-Chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), an Orally Active -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Antagonist, in Models of Generalized Epileptic Seizure in Mice and Rats

Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan

The anticonvulsant activity of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a novel -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.

Address correspondence to: Hiroshi Yamashita, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. E-mail: yamasita{at}yamanouchi.co.jp

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