肺动压是一类严重的血管性疾病，发病机制复杂，尚无药物能够完全治愈。内源性一氧化氮合成障碍是导致肺动脉收缩、痉挛的主要原因之一。研究表明，谷氨酸过度活化N-甲基-D天冬氨酸受体所介导的内皮细胞凋亡是肺动脉高压的一个重要病因。申请人在前期研究中合成了一系列美金刚硝酸酯衍生物。生物活性研究结果表明该类化合物既能保持对NMDA受体的较好的抑制作用，又能够快速分布于肺组织内，并且快速有效的释放NO。在肺动脉高血压大鼠模型中，该类化合物表现出较好的疗效，能够有效的降低肺动脉重构。受此启发，本项目拟进一步合成以金刚烷胺为母体的NONOate型NO供体化合物，并对其进行活性筛选，优选化合物将进一步在野百合碱诱导的大鼠肺动脉高压模型中进行疗效的评价，同时对化合物的构效关系进行分析和研究。通过本项目的研究，我们希望能够为后续治疗肺动脉高压的药物的设计、合成和开发提供指导。

Pulmonary hypertension (PH) is a serious cardiovascular disease and can not be complete cured up to now. The pathogenesis of PH is perplexing. The decrease of endogenous nitric oxide (NO) is one of the most important reasons of pulmonary artery vasoconstriction and vasospasm. The endothelial cells apoptosis induced by overactivation of N-methyl-D-aspartate (NMDA) receptor is proved to be another cause of PH. The applicant have synthesized a series of dual-functional memantine-nitrate compounds in previous study. The biological activity research revealed that compound MN-08 was effectively in antagonizing NMDA receptor, releasing NO and dilating constricted blood vessels. Compound MN-08 also distributed in lung fast and showed a potential to PH treatment in monocrotaline induced rat PH model. In this application, novel amantadine-NONOate compounds as NO donor were designed and the biological activities of these compounds will be explored. The effects and the mechanisms of the most potent compound will also be investigated. The structure-activity relationship of new compounds will be analysized. Through this research, we hope a more potent leader compound for PH treatment will be found, and the results of this research also provide us a guidance in future drug design.