芳基氨甲基-哌啶/四氢萘类μ/δ阿片受体双重功效镇痛分子成药性研究

Dual μ/δ functional opioid ligands have become the primary research direction for developing novel potent analgesics with diminished side effects or toxicities. With the eventual aim of discovering novel preclinical opioid analgesic candidates with dual actions targeted on μ and δ opioid receptors, the dual μ/δ functional opioid ligands FWB-16 and FWAS-011, and selective μ and δ opioid ligand FWB-27 and FWAS-011 discovered by us were taken as leads in this projects. Four series of 150 compounds were designed based on the binding mode of ligand with opiold receptor, the primary SAR and pharmacokinetics study. The designed compounds will be further synthesized and bio-tested at receptor and cellular level to provide valuable candidates with dual μ/δ functional activities for further druggability study and downstream G-protein pathway functional activity assays. We will select candidates with G-protein pathway biased properties, clarifying the molecular basis of μ agonist mediated signal transduction and identifying the molecular swiches for such dual functional activities. In this project, the advanced technique "fragment-based dynamical virtual screening" will be integrated with rational drug design strategy; multiple animal models will be carried out to evaluate the pharmacological and toxicological profiles of selectied candidates. The final aim of this project is to find the potential G-protein pathway biased μ/δ opioid candidates with novel scalffolds, which will be developed to be strong analgesia with clear mechanism of action, decent druggabilities, and diminished side effects for further preclinical study.

μ/δ双重功效阿片受体配基成为新一代强效低毒副作用镇痛药的主要研究方向。本项目以发现μ/δ双重功效阿片类临床前候选镇痛药物为目标，以课题组申请专利的新结构μ/δ双重功效阿片配基及μ或δ选择性阿片配基为先导物，根据前期获得的初步构效关系及PK等数据，共设计A-D四类约150个化合物进行化学合成、分子、细胞及动物水平体内外药效测试，从而优选高活性的μ/δ双重功效活性化合物进行深入的成药性研究及下游G蛋白通路功能研究，优选G蛋白偏向型μ/δ阿片受体配基，阐明其介导的μ阿片受体激活机制及其具有μ/δ双重功效的分子开关。同时本项目拟采用课题组最新发展的“基于片段的动态虚拟筛选技术”，结合多项动物镇痛实验、PK实验和各项体内毒副作用评价实验，旨在获得具有自主知识产权、作用机制新颖明确、成药性好、镇痛作用强、低毒低成瘾性的新型G蛋白偏向型μ/δ双重功效阿片类候选镇痛药物分子。

本项目研究了按照预期顺利完成了200个全新骨架芳基氨甲基-哌啶/四氢萘类阿片受体激动剂的设计、合成、药理测试和药代药动学研究。其中12个分子动物水平有高镇痛活性，最终获得有转让前景的成药性数据和分子机制完备的3个镇痛候选分子，成功地解决了血脑屏障通透的设计难题。最终开发出的化合物(3R,4S)-9d为强效镇痛剂，通过其O-去甲基化代谢物(3R,4S)-10a引发其有效的镇痛作用，其对映体(3R,4S)-9d与新型支架是其抗伤害活性的主要成分，其ED50值为0.54 mg/kg，在热板和抗扭体模型中为0.021 mg/kg。在本项目的资助下，发表了9篇高影响因子的SCI论文，申请了9项专利，申请1项PCT专利，授权专利3项，作为主编编著专著一部。