评价 6-(4-氯苯氧基)-四唑并[5,1-a]酞嗪在小鼠各种实验性癫痫模型中的抗惊厥活性。

Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various experimental seizure models in mice.

机构信息

Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Neimenggu, China.

出版信息

Pharmacol Rep. 2010 Mar-Apr;62(2):273-7. doi: 10.1016/s1734-1140(10)70266-8.

PMID:20508282

Abstract

This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) seizure model. The neurotoxicity of QUAN-0808 was investigated using the rotarod neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED(50) = 6.8 mg/kg) and lower neurotoxicity (median toxic dose, TD(50) = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED(50) = 24 mg/kg) against MES-induced seizure with low neurotoxicity (TD(50) > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against seizures induced by ISO, THIO and 3-MP.

摘要

本研究考察了一种新的酞嗪四唑衍生物 QUAN-0808（6-（4-氯苯氧基）-四唑并[5,1-a]酞嗪）在小鼠最大电休克（MES）惊厥模型中的抗惊厥活性。使用小鼠旋转棒神经毒性试验研究了 QUAN-0808 的神经毒性。QUAN-0808 表现出更高的活性（中位数有效剂量，ED50 = 6.8mg/kg）和更低的神经毒性（中位数毒性剂量，TD50 = 456.4mg/kg），与卡马西平（PI = 6.4）相比，保护指数（PI）更高（PI = 67.1）。此外，QUAN-0808 对 MES 诱导的惊厥具有显著的口服抗惊厥活性（ED50 = 24mg/kg），且神经毒性低（TD50 > 4500mg/kg），PI 值大于 187.5。QUAN-0808 还在化学诱导的动物惊厥模型（戊四氮[PTZ]、异烟肼[ISO]、硫代半卡巴腙[THIO]和 3-巯基丙酸[3-MP]）中进行了测试，以进一步研究其抗惊厥活性；QUAN-0808 对 ISO、THIO 和 3-MP 诱导的惊厥产生了显著的抗惊厥活性。