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Adv."],"published-print":{"date-parts":[[2026,2,13]]},"abstract":"<jats:p>\n                    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 \u03b4-opioid receptor and \u03bc-opioid receptor (\u03bcOR) 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-1\n                    <jats:italic toggle=\"yes\">H<\/jats:italic>\n                    -xanthene-1,8(2\n                    <jats:italic toggle=\"yes\">H<\/jats:italic>\n                    )-dione (MPAM-15), whose \u03b1\u03b2 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 \u03bcOR 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.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aea9832","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:58:47Z","timestamp":1770836327000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Structure-based design of an opioid receptor modulator for enhanced morphine analgesia"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3716-2922","authenticated-orcid":true,"given":"Yue","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China."},{"name":"Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese 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