新型含吡啶酮(吡唑)结构的A_(2a)/A_(2b)双靶点腺苷受体拮抗剂的合成及生物活性研究

Synthesis and Biological Activities of Novel A_(2a)/A_(2b) Dual-target Adenosine Receptor Antagonists Containing Pyridone or Pyrazole Structure

设计并合成了具有吡啶酮或吡唑结构的6个新型双靶点(A_(2a)和A_(2b))腺苷受体拮抗剂。其结构经^(1)H NMR、^(13)C NMR和HR-MS(ESI)表征。采用cAMP法评价了目标化合物(11a~11f)对A_(2a)和A_(2b)受体的抑制活性。活性测试结果表明:该系列化合物对A_(2a)和A_(2b)受体均有较好的抑制活性。其中化合物11e抑制活性最强,抑制A_(2a)和A_(2b)受体的IC_(50)值分别为8.188 nM和15.22 nM,11e对A_(2b) R受体的抑制活性优于阳性对照药AB928(IC_(50)=36.48 nM)。此外,利用分子对接研究了化合物11e与A_(2a)和A_(2b)靶点的结合情况,结果表明:化合物11e与A_(2a)和A_(2b)靶点具有较好的亲和作用。

Six dual-target(A_(2a) and A_(2b))adenosine receptor antagonists containing pyridone or pyrazole structure were designed and synthesized.The structures were characterized by ^(1) H NMR,^(13) C NMR and HR-MS(ESI).And cAMP functional assay was used to evaluate the inhibitory activities of synthesized compounds(11a~11f)against A_(2a) and A_(2b) receptors.The assay results showed that all compounds exhibit good to excellent inhibitory activities on A_(2a) and A_(2b) receptors.Compound 11e showed significant inhibitory activities against A_(2a) R and A_(2b) R,with the IC_(50) values of 8.188 nM and 15.22 nM respectively,and its inhibitory activity on A_(2b) R receptor is better than that of control drug AB928(IC_(50)=36.48 nM).Meanwhile,the interaction modes between 11e with A_(2a) R or A_(2b) R were studied by the molecular docking.Results showed that compound 11e has a good affinity for the A_(2a) and A_(2b) targets.