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  2. 上海药物研究所
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  4. 国家级研究中心
  5. 原创新药研究全国重点实验室
Structure-based design of an opioid receptor modulator for enhanced morphine analgesia

文献类型：期刊论文

作者Wang, Yue5,6; Luo, Ping5,6; Xu, Haiyan5; Zhan, Li5; Sakamoto, Kensuke7; Li, Mingyu1; Wang, Jing3,7; Huang, Xi-Ping3,7; Zhou, Jianhui1; Liu, Tao5,6
刊名SCIENCE ADVANCES
出版日期2026-02-11
卷号12期号:7页码:17
DOI10.1126/sciadv.aea9832
英文摘要The alarming rates of deaths due to opioid overdose present an urgent need for safer opioid analgesics. Positive allosteric modulators (PAMs) of opioid receptors (ORs) offer a promising approach to enhance opioid efficacy while reducing risks of overdose. In this study, we unveil the selective mechanism of PAM modulation of the OR family through structure elucidation of the delta-opioid receptor and mu-opioid receptor (mu OR) bound to orthosteric agonists and PAMs BMS986187 (BMS187) and BMS986122 (BMS122). In addition, we uncovered an unexpected but conserved allosteric site across the transmembrane helices TM2 to TM4 of ORs, occupied by BMS187 but not BMS122. Leveraging these structural insights, we designed 9-(5-(4-chlorophenyl)furan-2-yl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (MPAM-15), whose alpha beta cooperativity factor is 33-fold higher than BMS122 and threefold higher than BMS187, indicating markedly stronger positive allosterism. Animal studies demonstrate that MPAM-15 shows excellent brain penetration and enhances morphine-induced antinociception without exacerbating respiratory depression or constipation. Molecular dynamics simulations revealed that MPAM-15 promotes and stabilizes the conformational equilibrium of mu OR toward the canonical active state, providing a mechanistic basis for its enhanced allosteric potency. These discoveries substantially advance our understanding of OR allosteric mechanism and pave the way for the structure-based development of allosteric opioid analgesics.
WOS关键词POSITIVE ALLOSTERIC MODULATORS ; MOLECULAR-DYNAMICS ; DISCOVERY ; PHARMACOLOGY ; RECOGNITION ; SOFTWARE ; COMPLEX ; SITE
资助项目Natural Science Foundation of Shanghai, China[23ZR1475300] ; Young Elite Scientists Sponsorship Program by CAST[2023QNRC001] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82495184] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[92169202] ; National Natural Science Foundation of China[81925034] ; National Natural Science Foundation of China[32401002] ; National Key R&D Program of China[2019YFA0904200] ; National Key R&D Program of China[2022YFC2703105] ; National Key R&D Program of China[2022YFA1302900] ; National Key R&D Program of China[2024YFA1307504] ; CAS Strategic Priority Research Program[XDB37030103] ; CAS Strategic Priority Research Program[XDB0830000] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Lingang Laboratory[LG-GG-202204-01] ; State Key Laboratory of Drug Research[SKLDR-2023-TT-04] ; National Science Fund of Distinguished Young Scholars[81825021] ; Sailing Program of Shanghai Venus Project[23YF1456700] ; The Shanghai Jiao Tong University 2030 ; Youth Innovation Promotion Association of the Chinese Academy of Sciences ; HE Research Fellowship[HERF2025011] ; [WH510363003/017] ; [2023298]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001687313300001
出版者AMER ASSOC ADVANCEMENT SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/322969]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Zhang, Jian; Roth, Bryan L.; Gao, Zhaobing; Xu, H. Eric; Zhuang, Youwen
作者单位1.Shanghai Jiao Tong Univ, Sch Med, Dept Pharmaceut & Artificial Intelligence Sci, Shanghai 200025, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
3.Univ North Carolina Chapel Hill, Natl Inst Mental Hlth Psychoact Drug Screen Progra, Sch Med, Chapel Hill, NC 27599 USA
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China
7.Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA
推荐引用方式
GB/T 7714		 Wang, Yue,Luo, Ping,Xu, Haiyan,et al. Structure-based design of an opioid receptor modulator for enhanced morphine analgesia[J]. SCIENCE ADVANCES,2026,12(7):17.
APA Wang, Yue.,Luo, Ping.,Xu, Haiyan.,Zhan, Li.,Sakamoto, Kensuke.,...&Zhuang, Youwen.(2026).Structure-based design of an opioid receptor modulator for enhanced morphine analgesia.SCIENCE ADVANCES,12(7),17.
MLA Wang, Yue,et al."Structure-based design of an opioid receptor modulator for enhanced morphine analgesia".SCIENCE ADVANCES 12.7(2026):17.

入库方式： OAI收割

来源：上海药物研究所

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