吲哚哌啶-哌嗪类衍生物在α_1-肾上腺素受体介导的收缩反应中的生物学活性(英文)  

Bioactivity of indolylpiperidine-piperazine derivatives on α_1-adrenoceptor-mediated inotropic response

作　　者：李素芳[1] 刘飞[1] 刘巍[2] 赵悦[2] 吕志珍[1] 徐明[1] 张幼怡[1] 

机构地区：[1]北京大学第三医院血管医学研究所分子心血管教育部重点实验室,卫生部心血管分子生物学与调节肽重点实验室,北京100191 [2]北京大学化学与分子工程学院化学生物学系,北京100871

出　　处：《中国药理学与毒理学杂志》2012年第3期276-281,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：The project supported by National Natural Science Foundation of China(81070196);Natural Science Foundation of Beijing(7082101);Program for New Century Excellent Talents in University and Beijing Talents Foundation(BMU20100012)~~

摘　　要：目的检测一批新合成的α1-肾上腺素受体(α1-AR)拮抗剂对α1-AR的选择性拮抗活性。方法①通过吲哚哌啶与哌嗪分子耦合衍生,得到一系列α1-肾上腺素受体拮抗剂分子,化合物B1～B9,分别具有吲哚哌啶基和不同的取代基团。②应用离体大鼠左心耳收缩功能实验,检测IPD,化合物B1～B9对PE刺激下离体大鼠左心耳上α1-AR的拮抗活性。③采用Western印迹法检测IPD,化合物B1～B9对PE刺激下293细胞内细胞外信号调节激酶(ERK)磷酸化水平的影响。结果①成功合成了具有吲哚哌啶基和不同取代基团的潜在α1-AR拮抗剂。②提前孵育α1-AR拮抗剂酚妥拉明或IPD,化合物B1,B3,B4,B7,B8,B9,PE引起的离体大鼠左心耳的收缩反应均被有效抑制;其中IPD,化合物B4和B8引起收缩曲线的明显右移,IPD,化合物B4和B8的pA2值分别是6.72±0.21,6.86±0.29和6.67±0.19。③在稳定表达α1A-AR的HEK293细胞内,化合物B1,B2,B3,B5,B6,B7,B8,B9或IPD均较明显地抑制PE引起的ERK1/2的磷酸化增强;在稳定表达α1B-AR的HEK293细胞内,化合物B2,B4,B7或B8较明显地抑制PE引起的ERK1/2的磷酸化增强。结论化合物B4能够选择性地拮抗α1B-AR的活性;化合物B1,B3,B5,B6,B9和IPD能够选择性地拮抗α1A-AR的活性。OBJECTIVE To investigate the blocking activities of a series of potential t^l-adrenoceptor （Otl-AR） antagonists （Compounds B1 -B9） on a1-AR. METHODS ①A series of potential cq-adrenoceptor （cq-AR） antagonists, indolylpiperidine derivative （IPD） and Compounds B1 -B9, with indolylpiperidine moiety and different substitutes were synthesized through the coupling of indolylpiperidine and piperazine derivatives. ② Inotropic responses experiment was used to examine blocking effects of IPD and Compounds B1 - B9 in isolated rat atria by phenylephrine （PE） stimulation.③ Blocking effect of IPD and Compounds B1 -B9 on phosphorylation level of ex- tracellular signal-regulated kinase （ERK） in PE treated HEK293 ceils was tested by Western blotting. RESULTS ①Potential a1-adrenOceptOr （a1-AR） antagonists with indolylpiperidine moiety and different substitutes were syn-thesized successfully. ② PE caused a dose-dependent inotropic response which was inhibited by pre-incubation of phentolamine （Phen）, a non-selective a1-AR antagonist, IPD and Compounds B1, B3, B4, B7, B8 and B9, respectively ; IPD and Compounds B4 and B8 caused an obvious rightward shift of inotropic response-curve, the pA2 values for IPD and Compounds B4 and B8 were 6.72±0.21, 6.86±0.29 and 6.67±0.19, respectively. ③ Phosphorylation level of ERK1/2 was inhibited by pre-incubation with Compounds B1, B2, B3, BS, B6, B7, B8 and B9 or IPD in PE treated C1A-AR stably expressed HEK293 cells; PE-stimulated phosphorylati0n level of ERK1/2 was inhibited by pre-incubation with Compounds B2, B4, B7 or B8 in a1B-AR stably expressed HEK293 cells. CONCLUSION Compound B4 has a selective blocking activity on a1B-AR, and Compounds B1, B3, BS, B6 and B9 or IPD have a selective blocking activity on the phosphorylation level of ERK1/2.

关 键 词：受体 肾上腺素 α1肾上腺素受体拮抗剂 吲哚哌啶-哌嗪衍生物 

分 类 号：R96[医药卫生—药理学]