目前绝大多数骨质疏松治疗药以抑制骨吸收为主，促进骨形成的仅有甲状旁腺素，还没有两者兼具的双重作用药物。肠源性血清素具有抑制骨形成作用，其合成初始酶1型色氨酸羟化酶（Tph-1）是骨形成促进剂的新型设计靶标。申请人从天然产物齐墩果酸的衍生物中发现了一个具有较强抑制骨吸收活性的分子QOA-8a，有意思的是发现该分子还能抑制Tph-1活性、促进骨形成，具有双重作用。本项目在保持抗骨吸收活性基础上以Tph-1为靶标，分子对接技术为手段，发展理论辅助设计导向性高效绿色合成策略，构建以QOA-8a为基础的新颖化合物；研究化合物与Tph-1的相互作用，阐明构效关系，指导理性合成，着重提高促进骨形成活性；选择兼具抑制骨吸收和促进骨形成活性的化合物进行动物体内验证、深层次双重作用独特信号通路影响的研究，最终得到1-2个新型抗骨质疏松分子。本项目可为拥有自主知识产权的创新型抗骨质疏松药物的研发奠定基础。

Currently, the most clinically available antiosteoporosis therapies are antiresorptive agents, available anabolic one is only recombinant human parathyroid hormone (PTH), while there is still no drug with dual effects. Gut-derived serotonin (GDS) inhibits bone formation and its initial biosynthesis enzyme, tryptophan hydroxylase-1 (Tph-1) is a novel target for the anabolic agents design. From the derivatives of a natural product oleanolic acid, we discovered a compound QOA-8a that possessed potent anti bone resorptive effect. More interesting thing is this compound possesses dual effects with inhibiting Tph-1 activity and accelerating bone formation. The current project aims at developing the green synthesis strategy guided by molecular docking method that targets Tph-1, constructing novel compounds, while keeping the antiresorptive activity. Through detailed evaluation of interaction between the compounds and Tph-1, the project also points to clarifying the structure-activity relationship, guiding the rational syntheses and especially improving the anabolic activity. Furthermore, the current work is to examine the in vivo effects of the compounds possessing dual antiresorptive and anabolic properties, and also their influence on unique signal pathways with the dual effects. The final goal of the project is to discover 1-2 novel antiosteoporosis molecules. The results of the current project would lay a proper foundation for the development of innovative antiosteoporosis drugs with intellectual property rights.