新型磷酸二酯酶4变构调节剂氯比普兰改善学习记忆障碍的机制研究

磷酸二酯酶4(PDE4)抑制剂在改善学习记忆障碍中具有重要作用，但严重的呕吐反应阻碍其临床应用。氯比普兰是本课题组以PDE4变构调节理论为基础自主合成的新型PDE4变构调节剂。前期研究发现:氯比普兰对PDE4D4和PDE4D5的选择性显著低于咯利普兰，增强学习记忆的同时，氯比普兰不具有明显的致呕吐反应。这提示氯比普兰可能是一类新型PDE4抑制剂。目前，氯比普兰调节靶点蛋白活性的起效模式以及改善学习记忆障碍上的优越性和作用机制还不清楚。本项目在前期工作的基础上，将以第一代PDE4抑制剂咯利普兰和第二代PDE4抑制剂罗氟司特为对照物，探讨新型PDE4抑制剂氯比普兰对PDE4活性的双门控调节方式；同时以咯利普兰为参照物，阐明氯比普兰改善学习记忆障碍作用的优越性及作用机制的异同；初步探索传统PDE4抑制剂引起呕吐反应的可能机制。该项目的开展将为PDE4抑制剂的合理设计和临床应用产生重要意义。

Phosphodiesterase 4 inhibitors are a new class of potential cognitive enhancers in ameliorating learning and memory deficits, while the side effect of causing emesis limits their clinical application. Chlorbipram is a novel phosphodiesterase 4 allosteric modulator synthesized by our research team based on the theory of allosteric regulation. Our previous studies showed that the selectivity of chlorbipram to PDE4D4 or PDE4D5 was significantly lower than that of rolipram. Chlorbipram significantly enhanced cognitive ability in mice,however,it hardly led to obvious nausea and emesis in Beagle dogs, these data indicated that chlorbipram may play its role by new mechanisms that differ from the PDE4 inhibitor rolipram. Currently, the advantages and mechanisms of chlorbipram-mediated improvement of learning and memory are still not clear. Based on our previous project, we will explore the dual regulatory model of chlorbipram on PDE4 activity. Meanwhile,the advantages and mechanisms of chlorbipram on the enhancement of learning and memory will be conducted in comparison with the first generation PDE4 inhibitor rolipram and/or second generation PDE4 inhibitor roflumilast. We will also try to investigate the cause of emesis induced by classic PDE4 inhibitors, which will provide directions for rational design of PDE4 inhibitors and candidate drug screening targeting on PDE4.