3H-喹唑啉-4-酮衍生物的设计、合成及其α7尼古丁乙酰胆碱受体正向变构调节作用评价

摘要

作者基于课题组先前得到的具有较强α7烟碱型乙酰胆碱受体Ⅰ型正向变构调节剂活性的先导化合物2,设计并合成了一系列的6位取代的3H-喹唑啉-4-酮化合物(3a-3d),所有目标化合物均通过对表达有人源α7乙酰胆碱受体的非洲爪蟾卵使用双电极电压钳技术来进行活性评价.然而,在100 μM的乙酰胆碱作用下,所有化合物均没有显示出比先导化合物2更高的活性.由此证明噻唑[4,5-d]并嘧啶-7(6H)-酮母核是发挥正向变构调节活性的必需基团,是对先导化合物2的构效关系的补充.%A series of new 6-substituted 3H-quinazolin-4-ones (3a-3d) were designed,synthesized and evaluated as the type 1 positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus ooctyes by two-electrode voltage clamp.However,no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine (100 μM).The structure-activity relationship (SAR) analysis suggested that thiazolo[4,5-d]pyrimidin-7(6H)-one was the key biological skeleton.