基于Cym04激活BKCa钾通道分子机制的新型特异性开放剂的设计与合成

Well-characterized tissue- and function-specific BK channel openers not only are expected to have therapeutic potential for post-stroke neuroprotection and hyperpolarization of smooth muscles, but also should be of assistance in understanding the function, structure and role of BK channels. Although many natural and artificial compounds have been reported to show BK channel-opening activity, their activities are rather weak and nonspecific to BK channels. And scaffolds for the molecular design of BK channel openers are still limited. Moreover, little is known about the site(s) of interaction of openers of these channels.The aims of my proposed research are BK channel modulators identification with the long-term goal of developing potent and selective BK channel openers for therapeutic applications on the basis of our recent findings that Cym04 activates BK channels by functionally interacting with the S6/RCK linker, mimicking site-specific shortening of this purported passive spring, which transmits force from the cytosolic gating ring structure to open the channel's gate.

组织及功能特异性的BKCa 通道开放剂在缺血性脑中风时保护神经元免受损伤和/或抑制平滑肌组织过度兴奋中具有潜在的应用价值。至今为止，尽管已经发现了多种直接激活BKCa通道的化合物，但大部分活性不高，结构类型有限且对BKCa 通道无选择性。Cym04是我们发现的BKCa通道新型开放剂，其（小分子开放剂）激活BKCa通道的分子机制首次被阐明。本项目拟在Cym04激活BKCa通道分子机制的基础上，通过合理分子设计、化学合成和电生理等方法和技术，研究Cym04及其类似物的构效关系，进一步发现具有全新结构类型的高活性、高选择性、类药性好的BKCa通道开放剂，为确证BKCa作为药物靶标的可能性以及治疗心脑血管疾病的药物研发奠定基础。

本研究在Cym04激活BKCa通道分子机制的基础上，对树脂酸不同结构域进行了研究，设计合成了数百个新型的树脂酸衍生物并对所合成化合物进行了BKCa通道开放活性的筛选及构效关系研究，获得了数个结构新颖的高活性BKCa开放剂，部分化合物对由谷氨酸诱导的大鼠小脑颗粒神经元细胞损伤具有保护作用。本研究所发现的一些不同条件（如细胞静息、细胞去极化或/和高浓度Ca2+）下的高活性、高选择性、细胞通透性优良、类药性好的组织及亚型特异性BKCa通道开放剂，不仅有助于阐明BKCa通道在生理病理条件下的作用机制，而且有望找到新型的先导化合物作为血管性疾病治疗药物研究的起点。