Bioactivity of indolylpiperidine-piperazine derivatives on α1 -adrenoceptor-mediated inotropic response / 中国药理学与毒理学杂志

ABSTRACT

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.