Antinociceptive activity of new imidazolidine carbonyl derivatives.: Part 4.: Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo[2,1-c] [1,2,4]triazines
Antinociceptive activity of new imidazolidine carbonyl derivatives.: Part 4.: Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo[2,1-c] [1,2,4]triazines
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DOI：
10.1016/j.ejmech.2004.09.020
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发表时间：
2005-02-01
影响因子：
6.7
通讯作者：
Matosiuk, D
中科院分区：
文献类型：
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作者：
Sztanke, K;Fidecka, S;Matosiuk, D
报道了8-芳基-3，4-二氧代-2H，8H-6，7-二氢咪唑并[2，1-c] [1，2，4]三嗪（A）的合成及其药理活性。1-芳基-2-肼基咪唑啉（1）与草酸乙酯（2）环合得到标题化合物。在行为动物试验（A1、A3、A5、A6、A8、A9）中检测其药理活性。急性毒性相对较低（腹腔注射，LD 50为1100至2000 mg/kg以上），如“扭体”试验结果所示，它们中的一些显示出显著的抗伤害感受活性。分别在12.5-200 mg（0.00625-0.1 LD 50）和37.5-150 mg（0.025- 0.1 LD 50）的剂量下观察到化合物A8的特别强的抗伤害感受和A6的显著的抗伤害感受。在扭体实验中，5 mg kg（-1）剂量的纳洛酮可逆转A1和A8的抗伤害感受作用，这可能表明其镇痛活性的阿片样机制。此外，化合物A9减少了5-羟基色氨酸（5-HTP）给药后“头部抽搐”发作的次数，完全没有抗伤害感受作用，化合物A3在戊基美曲唑诱导的癫痫发作模型中显示出显著的保护作用。在A8和A9衍生物之间观察到的活性谱的差异可以基于在这两种化合物之间观察到的酰胺基-酰亚胺基互变异构平衡的差异来解释。(C)2004年，Elsevier SAS。All rights reserved.
Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo[2,1-c] [1,2,4]triazines (A) are presented. The title compounds were obtained from 1-aryl-2-hydrazinoimidazolines (1) by cyclization reaction with ethyl oxalate (2). They were tested for pharmacological activity in behavioral animal tests (A1, A3, A5, A6, A8, A9). With relatively low acute toxicity (LD50 in range from 1100 to over 2000 mg kg(-1), intraperitoneally, i.p.), some of them exhibited significant antinociceptive activity as the result of the 'writhing' test indicated. Especially strong antinociception for compound A8 and significant for A6 was observed in doses of 12.5-200 mg (0.00625-0.1 LD50) and 37.5-150 mg (0.025-0.1 LD50), respectively. Reversion of the antinociception for A1 and A8 produced in the 'writhing' test by 5 mg kg(-1) dose of naloxon can suggest an opioid-like mechanism of their analgesic activity. Additionally, compound A9 reduced number of the "head twitch" episodes after 5-hydroxytryptophan (5-HTP) administration with no antinociceptive effect at all and compound A3 showed significant protection in the pentylemetrazol-induced seizure model. Differences observed in the activity spectrum between A8 and A9 derivatives can be explained on the base of difference in the amido-imido tautomeric equilibrium observed between these two compounds. (C) 2004 Elsevier SAS. All rights reserved.