CAJ | 학술논문

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印迹法榆测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.
목적 검측일비신합성적α1-신상선소수체(α1-AR)길항제대α1-AR적선택성길항활성.방법 ①통과신타고정여고진분자우합연생,득도일계렬α1-신상선소수체길항제분자,화합물B1～B9,분별구유신타고정기화불동적취대기단.②응용리체대서좌심이수축공능실험,검측IPD,화합물B1～B9대PE자격하리체대서좌심이상α1-AR적길항활성.③채용Western인적법유측IPD,화합물B1 ～ B9대PE자격하293세포내세포외신호조절격매(ERK)린산화수평적영향.결과 ①성공합성료구유신타고정기화불동취대기단적잠재α1-AR길항제.②제전부육α1-AR길항제분타랍명혹IPD,화합물B1,B3,B4,B7,B8,B9,PE인기적리체대서좌심이적수축반응균피유효억제；기중IPD,화합물B4화B8인기수축곡선적명현우이,IPD,화합물B4화B8적pA2치분별시6.72±0.21,6.86±0.29화6.67±0.19.③재은정표체α1A-AR적HEK293세포내,화합물B1,B2,B3,B5,B6,B7,B8,B9혹IPD균교명현지억제PE인기적ERK1/2적린산화증강；재은정표체α1B-AR적HEK293세포내,화합물B2,B4,B7혹B8교명현지억제PE인기적ERK1/2적린산화증강.결론 화합물B4능구선택성지길항α1B-AR적활성；화합물B1,B3,B5,B6,B9화IPD능구선택성지길항α1A-AR적활성.
OBJECTIVE To investigate the blocking activities of a series of potential α1-adrenoceptor (α1-AR) antagonists (Compounds B1 -B9) on α1-AR.METHODS ① A series of potential α1-adrenoceptor (α1-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 extracellular signal-regulated kinase (ERK) in PE treated HEK293 cells was tested by Western blotting.RESULTS ① Potential α1-adrenoceptor (α1-AR) antagonists with indolylpiperidine moiety and different substitutes were synthesized successfully.② PE caused a dose-dependent inotropic response which was inhibited by pre-incubation of phentolamine (Phen),a non-selective α1-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,B5,B6,B7,B8 and B9 or IPD in PE treated α1A-AR stably expressed HEK293 cells; PE-stimulated phosphorylation level of ERK1/2 was inhibited by pre-incubation with Compounds B2,B4,B7 or B8 in α1B-AR stably expressed HEK293 cells.CONCLUSION Compound B4 has a selective blocking activity on α1B-AR,and Compounds B1,B3,B5,B6 and B9 or IPD have a selective blocking activity on the phosphorylation level of ERK1/2.