In our previous work, 5-hexyloxy- [ 1,2,4 ] triazolo [ 4,3-a ] quinoline ( compound Ⅰ ) showed potent anticonvulsant activity ,with ED50 value of 19.0 mg·kg- 1 and protective index( PI = TD50/ED50 ) values of 5.8 in the MES test. As part of our continuous effort to find better anticonvulsant candidate in this area,twelve derivatives of leading compound Ⅰ were synthesized by the modification of 1,2, and 5 positions of it. In addition, their anticonvulsant activity and neurotoxicity were evaluated using the MES test and the rotarod test in mice ,respectively. In the same condition, the 50％ toxic dose( TD50 ) and 50％ effective dose (ED50) of the reference drugs carbamazepine and the leading compound Ⅰ were evaluated in MES test and the rotarod test in our laboratory. The results of pharmacological tests demonstrated that some target compounds ( 6a, 10a, 10b) displayed anticonvulsant activities in different doses, and 5-hexyloxy-1 -methyl- [ 1,2,4] triazolo[4,3-a] quinoline(10b) showed good activity with an ED50 value of 18.0 mg·kg -1 and protective index ( PI = TD50/ED50 ) value of 7.9. The anticonvulsant activity ( ED50 and PI) of 10b is better than that of the leading compound Ⅰ. Compared to the reference drugs, compound 10b exhibited the weaker activity ,while it possessed the higher PI value ,which mean that compound 10b is safer than marketed drug carbamazepine.%目的 设计合成一系列1,2,4-三唑并[4,3-a]喹啉衍生物,并评价其抗惊厥活性和神经毒性.方法 以4-羟基喹啉-2(1H)酮为起始原料,经烷基化、氯代、肼代、环合等反应合成1,2,4-三唑并[4,3-a]喹啉衍生物.通过最大电惊厥实验(MES)和旋转棒法(Rotarod),分别测定目标化合物的抗惊厥活性和神经毒性.结果 合成了12个新化合物,其结构经1H-NMR、EI-MS和IR谱确证.结论 药理学实验结果表明,部分化合物在不同剂量下显示出抗惊厥活性,其中,5-苄氧基-1-甲基-[1,2,4]三唑并[4,3-a]喹啉(10b)的活性最强,其半数有效量ED50值为18.0 mg·kg-1,保护指数PI为7.9,虽然该化合物的活性低于阳性对照药卡马西平,但其保护指数优于卡马西平(PI=6.4),有进一步研究的价值.
展开▼
