本项目以具有D1及D3受体双重激动作用新型抗帕金森候选化合物发现为目标，以我们通过合理药物设计发现的全新结构类型D1和D3激动剂FD03-007-2，FW-X02-4，FW02-084-4及FW-DP-18为先导化合物，基于初步构效关系及分子作用机制设计A-G七个系列120个左右化合物进行合成及分子水平、细胞水平药理毒理测试，确定有苗头的新结构类型候选分子进行深入的成药性研究，并阐明苗头分子与受体的作用方式及转导多巴胺受体信号的分子基础。本项目运用前沿的动态虚拟筛选及基于片段的虚拟筛选等技术，结合抗帕金森症动物行为学等实验，发现更多新结构类型具有优良PD/PK性质的候选分子，旨在获得具有自主知识产权、作用机制明确、成药性好的新结构类型抗帕金森症候选化合物进入临床前研究。

This project takes design of novel anti-Parkinson's candidates targeted on dopamine D1 and D3 receptors as research object, and takes D1 agonists FD03-007-2 and FW-X02-4 which bear new structures and better solubility reasonably designed by optimizing the structure of l-SPD, and D3 inhibitors FW02-084-4 and FW-DP-18 with high activity discovered by reasonable computer aided drug design as lead compounds. 120 compounds with seven series are designed based on primary SAR and molecular mechanism of action, synthesized and tested by molecular and cellular pharmacological and toxicological assays to screen valuable candidates with novel structures for primary pharmacokinetic research and simulation research aimed at clarifying the interaction mode between the compounds and receptors and molecular basis of D1 agonist mediated signal transduction. In the meantime, prediction of protein structure, molecular docking, molecular dynamics simulation, dynamic virtual screening and fragment-based virtual screening are integrated with the purpose of discovering more new structural target molecules. The result of our research lays a foundation for researching and developing novel anti-Parkinson's drugs and offers a certain amount of anti-Parkinson's candidates with novel structures, clear mechanism of action and primary pharmacological and pharmacokinetic data.