基于结构的CB2受体激动剂的设计合成与抗肝纤维化活性研究

大麻素受体介导的信号通路在肝炎和脂肪肝引起的肝纤维化中发挥关键作用，激动CB2受体可以引发抗炎活性、降低肝实质细胞的增殖进而抑制肝纤维化发生发展。相反，激动CB1受体会促进肝纤维化发展，同时引起严重中枢神经副作用，因此选择性激动CB2受体被认为是治疗肝纤维化的潜在新策略。本项目拟在前期获得的吲哚甲酰胺类CB2受体配体基础上，结合已经解析的CB2受体晶体结构，合理设计开发一系列新颖的选择性CB2受体激动剂用于开展抗肝纤维化研究。通过系统评价合成化合物对CB2受体的活性、选择性、偏向性，并考察化合物ADMET和药代动力学性质，挑选出活性好、成药性高的先导化合物。阐明相关分子作用机制及对下游信号通路的影响，同时在多种肝纤维化动物模型上评价优选化合物的抗肝纤维化药效，检测血液中肝功能相关生化指标及肝纤维化相关标志物的表达量，评价化合物缓解肝纤维化及相关炎症的效果，为肝纤维化治疗提供新的思路和选择。

Endocannabinoids and their receptors have emerged as major regulators of several pathophysiological aspects associated with chronic liver disease progression such as viral hepatitis, fatty liver disease, and liver fibrosis. Emerging evidence has demonstrated that activation of CB2 receptor resulted in anti-inflammatory effects and reduced hepatocyte proliferation, which inhibited the occurrence and development of liver fibrosis. On the contrary, activation of CB1 receptor can promote the progression of liver fibrosis and lead to severe psychiatric adverse effects. Thus, the development of novel ligands targeting CB2 receptor with high potency and selectivity may hold the promise to fulfill the unmet clinical need of liver fibrosis while avoiding the psychotropic side effects caused by the interaction with CB1 receptor. On the basis of our previously reported amidoalkylindole CB2 ligands and the crystal structure of CB2 receptor, a series of novel CB2 agonists were designed, synthesized, and biologically evaluated for their potency, selectivity, and bias activity against the CB2 receptor, as well as preliminary ADMET and pharmacokinetics profiles. Some lead compounds were chosen for further molecular mechanism study and evaluated for their efficacy in several animal models of liver fibrosis. Overall, this project laid a solid foundation for the potential application of selective CB2 agonists for the treatment of liver fibrosis and provided new thoughts and choices for this disease.