摘要
根据尼卡地平结构特征，设计并合成了三个衍生物，化合物代号分别为９２０１、９２０２和９２０３。在体外血管、工作心脏和清醒大鼠多种实验模型上，研究这三个新化合物对心血管系统的作用特点。在大鼠主动脉环上，尼卡地平、９２０１、９２０２和９２０３抗氯化钾４０ｍｍｏｌ／Ｌ缩血管作用的ＥＣ５０值分别为１．１，０．４，１．２，７．２μｍｏｌ／Ｌ；抗氯化钙２５ｍｍｏｌ／Ｌ缩血管作用的ＥＣ５０值分别为４６，６，１．１，２．８μｍｏｌ／Ｌ；浓度在０．１～１００μｍｏｌ／Ｌ范围内，不对抗去甲肾上腺素５．５μｍｏｌ／Ｌ诱发血管收缩的作用；浓度增至１０ｍｍｏｌ／Ｌ也不对抗去甲肾上腺素０．６μｍｏｌ／Ｌ在无钙孵育液中的缩血管效应。在大鼠工作心脏上，９２０２作用强度与尼卡地平相当，浓度在０．１～１．０μｍｏｌ／Ｌ时可减慢心率，抑制心脏收缩和舒张功能，９２０１和９２０３的作用比尼卡地平弱９０％以上。在清醒大鼠上，灌胃给予尼卡地平及其三个衍生物３ｍｇ／ｋｇ均可使收缩压下降２．０～２．７ｋＰａ，降压至少可持续３ｈ，且对心率的影响轻。提示尼卡地平及这三个衍生物具有较强的扩血管作用，其中９２０１和９２０３对心脏的作用较轻，口服可产生确切的降压效应。
Compounds 9201, 9202 and 9203 were designed and synthesized according to the structural characteristics of nicardipine. In this experiment, the cardiovascular effects of the three new compounds were investigated in isolated aorta, isolated working hearts and conscious rats. The EC 50 values of nicardipine and compound 9201, 9202 and 9203 for dilating the aorta precontracted with 40 mmol/L potassium chloride were 1.1, 0.4, 1.2 and 7.2 μmol/L respectively, while the values of EC 50 for dilating the arota precontracted with 25 mmol/L calcium chloride were 46, 6, 1.1 and 2.8 μmol/L respectively. These compounds at the concentrations of 0.1-100 μmol/L could neither dilate the aorta precontracted with 5.5 μmol/L norepinephrine, nor dilate the aorta precontracted with 0.6 μmol/L norepinephrine in Ca 2+ free solution even if the concentration was increased to 10 mmol/L. On isolated working hearts of rats, the compound 9202 and nicardipine at the concentrations of 0.1-1.0 μmol/L decreased the heart rates and inhibited the systolic and diastolic functions. But the effects of compound 9201 and 9203 were over 10 times weaker than those of nicardipine. These four compounds at 3 mg/kg po reduced the systolic blood pressure by 2.0-2.7 kPa in conscious rats, and the hypotensive action lasted three hours at least. They didnot affect the heart rates significantly. These results suggest that the three novel derivatives of nicardipine have potent vasodilative effects, relatively weak cardiac effects and moderate hypotensive effects.
出处
《军事医学科学院院刊》
CSCD
北大核心
1997年第1期5-9,共5页
Bulletin of the Academy of Military Medical Sciences
基金
军事医学科学院新药研究基金
关键词
降压剂
尼卡地平
钙离子通道
拮抗剂
antihypertensive agents
nicardipine
calcium channels
antagonists
