Gs信号通路选择性β2受体激动剂的设计、合成及其抗心力衰竭活性研究

Cardiovascular disease has become an important public health problem in our country as its prevalence and mortality remain high in recent years with an increasing prevalence of the more malignant forms of the disease such as heart failure and painless myocardial infarction. Thus, discovering new drugs for the prevention and treatment of cardiovascular disease is an urgent and major scientific concern for our country. Recent studies suggest that phosphorylation of the β2-adrenoceptor by GRK2 leads to the coupling of Gi proteins and exaggerates Gi-biased signaling, a major causative factor for maladaptive cardiac remodeling, heart failure and heart dysfunction. Biased signaling at theβ2-adrenoceptor may be a potential therapeutic target in heart failure. Further exploration of this potential in this classical drug target and making breakthroughs in the discovery of new functions and new uses will provide new treatment options for patients with heart failure. New compounds with high potency and selectivity for the β2-adrenoceptor Gs pathway will be derived from structural modification of lead compounds from our previous work and also from a structure-based approach guided by computer-aided drug design. Interactions of the β2-adrenoceptor with these compounds at the molecular level will be studied by combining structure-activity relationship and characterization of ligand binding mode. Pharmacological actions and biological mechanisms of the hit compounds will be further studied to evaluate the potential usefulness of pathway selectiveβ2-adrenoceptor activation in clinical practice. The goal of the present study is to discover new drugs for heart failure.

近年来，我国心血管疾病的发生率和死亡率居高不下,特别是心力衰竭和无痛性心梗死亡率很高，针对防治心血管疾病的创新药物的研究是亟待解决的重大科学问题。最新发现GRK2磷酸化β2-AR导致受体偶联Gi蛋白及激活Gi偏向性信号转导是引起适应不良性心脏重塑、心衰和心功能障碍的关键环节，β2-AR功能选择性信号转导可能是潜在的心力衰竭治疗新靶标。探索成熟药靶β2受体的新功能新用途，实现其治疗价值上的新突破，会给心力衰竭患者提供全新的治疗方案。在前期工作基础上，结合β2受体结构信息和计算机辅助模拟指导，对已发现的先导化合物进行结构修饰，以期得到Gs通路选择性活性更好的β2受体激动剂，并进行构效关系总结，在分子水平上研究激动剂和β2受体结合作用模式，进一步探索其药理作用机制和评价β2受体通路选择性活性的临床应用价值，发现新型抗心力衰竭药物。

近年来，我国心血管疾病的发生率和死亡率居高不下,特别是心力衰竭和无痛性心梗死亡率很高，针对防治心血管疾病的创新药物的研究是亟待解决的重大科学问题。最新发现GRK2磷酸化β2-AR导致受体偶联Gi蛋白及激活Gi偏向性信号转导是引起适应不良性心脏重塑、心衰和心功能障碍的关键环节，β2-AR功能选择性信号转导可能是潜在的心力衰竭治疗新靶标。. 在前期工作基础上，通过对1-苯基-2-氨基乙醇类和2-苯基-2-氨基乙醇类β2受体激动剂的研究和开发，我们新发现3个β-arrestin偏向性β2受体激动剂，药理研究显示它们都具有保护心肌细胞的作用。另外，对临床抗哮喘药沙美特罗(Salmeterol)是Gs偏向性还是β-arrestin偏向性一直存在争议，我们以更具说服力的数据支持沙美特罗是Gs偏向性β2受体激动剂，对发展信号通路选择性的抗心衰和抗哮喘药具有重要指导意义。研究发现MNF在小鼠整体心脏和心肌细胞都能减少抗肿瘤药物阿霉素、氧化应激或缺血再灌注等多种损害。同时，我们以上市药物长效β2受体激动剂茚达特罗、奥达特罗和沙美特罗为先导，采用基于结构和靶标的药物设计原理，通过骨架跃迁、电子等排等方法，设计并合成4类新型β2受体激动剂150余个，已获得EC50值达到皮摩尔级别的化合物。. 本项目相关研究成果发表SCI期刊论文8篇，会议论文1篇，分别发表在Journal of Medicinal Chemistry（2篇，其中1篇为封面文章），European Journal of Medicinal Chemistry（1篇），Expert Opinion on Therapeutic Patents（1篇），Bioorganic & Medicinal Chemistry（2篇）和Circulation Research（1篇），Acta Pharmacologica Sinica（1篇），The FASEB Journal（1篇）。培养2名博士研究生和6名硕士研究生。