新化合物SIPI5052对离体血管收缩功能影响.docVIP

新化合物SIPI5052对离体血管收缩功能影响 　【摘要】 目的 为了了解抗脑缺血新化合物SIPI5052是否具有钙拮抗作用，本研究观察它对去甲肾上腺素或高钾诱导的离体血管收缩功能的影响。方法 采用计算机化离体血管功能测定系统观察SIPI5052对离体大鼠胸主动脉、家兔胸主动脉和肠系膜动脉收缩功能的影响。结果 SIPI5052可明显抑制受试血管去甲肾上腺素或高钾诱导的收缩反应，呈剂量依赖性。在大鼠血管上，起效浓度为3×10-6mol/L，IC50为1.66×10-4mol/L，100%抑制浓度为3×10-3mol/L。在家兔血管上，起效浓度为3×10-4mol/L，IC50为4.17×10-4~5.37×10-4mol/L，100%抑制浓度≥3×10-3mol/L。结论 SIPI5052具有钙拮抗作用。大鼠血管对SIPI5052的反应较家兔血管敏感。钙拮抗作用很可能是SIPI5052的抗脑缺血作用机制之一。 【关键词】 哌嗪类；主动脉；肠系膜动脉；收缩反应；钙通道；抗脑缺血 Effect of SIPI5052，a new chemical entity，on the contraction of isolated arteries 【Abstract】 Objective To study the effect of a new anti-stroke chemical entity SIPI5052 on Ca2+ channels，by observing its effect on norepinephrine or KCl induced contraction in isolated blood vessels.Methods Using IOX computerized system (EMKA Technologies，Paris，France) to record the changes of isometric tension in isolated rat aorta，rabbit aorta and rabbit mesenteric artery.Results SIPI5052 can significantly inhibit norepinephrine or KCl induced contraction in the examined blood vessels and the effect is concentration-dependent.The minimum inhibitory concentration in rat aorta is 3×10-6mol/L，with the IC50value of 1.66×10-4mol/L.The minimum inhibitory concentration in rabbit aorta and mesenteric artery is 3×10-4mol/L，and the IC50value is between 4.17×10-4 and 5.37×10-4mol/L.Conclusion SIPI5052 can block Ca2+ channels.Rat isolated blood vessels are more sensitive to SIPI5052 than rabbit isolated blood vessels.Ca2+ channel blocking may be involved in the anti-stroke action of SIPI5052. 【Key words】 piperazidines; aorta; mesenteric artery; contraction; calcium channel; anti-cerebral ischemia SIPI5052属芳烷甲酰基哌嗪类结构，化学名为N1-苯甲酰甲基-N4-苄胺甲酰甲基哌嗪二盐酸盐。本品是上海医药工业研究院定向设计、合成、筛选出的兼有抗局灶性脑梗死作用和对受损脑神经元有保护功能的全新化合物［1］。SIPI5052已获得中国发明专利授权，专利号为：ZL8，亦已申请美国和欧洲专利，申请号分别为10/513，6997。SIPI5052作为抗脑中风急救用药正在进行一期临床试验，国家食品药品监督管理局的批件号为2006L01411，被批准的药品名为盐酸非那嗪奈。SIPI5052可能成为新一代NMDA受体多胺调节位点拮抗剂，但目前其脑神经保护作用机理不甚明确。初步的机制研究显示其抗脑缺血的作用与拮抗ADP诱导的血小板聚集无关，并且SIPI5052抗NMDA受体的