2. Academic Validation
  3. Structure-based design of an opioid receptor modulator for enhanced morphine analgesia

Structure-based design of an opioid receptor modulator for enhanced morphine analgesia

  • Sci Adv. 2026 Feb 13;12(7):eaea9832. doi: 10.1126/sciadv.aea9832.
Yue Wang 1 2,  Ping Luo 1 2,  Haiyan Xu 1,  Li Zhan 1,  Kensuke Sakamoto 3,  Mingyu Li 4,  Jing Wang 3 5,  Xi-Ping Huang 3 5,  Jianhui Zhou 4,  Tao Liu 1 2,  Yanrui Suo 1,  Wenjia Fan 1 2 6,  Xinheng He 1 2 7,  Youwei Xu 1 2,  Yongjie Cai 1,  Chao Wang 1,  Yuxi Zhao 1 2 6,  Antao Dai 1,  Yali Lai 1 2 7,  Qingning Yuan 1 6,  Wen Hu 1,  Kai Wu 1,  Dehua Yang 1,  Xi Cheng 1,  Xiaojie Lu 1,  Brian Krumm 3,  Terry Kenakin 3,  Jian Zhang 4,  Bryan L Roth 3 5,  Zhaobing Gao 1,  H Eric Xu 1 2 6 7,  Youwen Zhuang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 4 Department of Pharmaceutical and Artificial-Intelligence Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 5 The National Institute of Mental Health Psychoactive Drug Screen Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 6 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 7 University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 41671375 DOI: 10.1126/sciadv.aea9832
Abstract

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 δ-opioid receptor and μ-opioid receptor (μOR) 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 αβ 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 μOR 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.

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