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TitleA µ-opioid receptor superagonist analgesic with minimal adverse effects.
Journal, issue, pagesNature, Year 2026
Publish dateApr 1, 2026
AuthorsJuan L Gomez / Emilya N Ventriglia / Zachary J Frangos / Agnieszka Sulima / Michael J Robertson / Michael D Sacco / Reece C Budinich / Ilinca M Giosan / Tongzhen Xie / Oscar Solis / Anna E Tischer / Jennifer M Bossert / Kiera E Caldwell / Hannah Bonbrest / Amelie Essmann / Zelai M Garçon-Poca / Shinbe Choi / Michael R Noya / Feonil Limiac / Ali Arce / Grant C Glatfelter / Margaret Robinson / Li Chen / Angelina A Mullarkey / Dain R Brademan / Garrett Enten / William Dunne / César Quiroz / Ingrid Schoenborn / Chae Bin Lee / Rana Rais / Daniel P Holt / Robert F Dannals / Lei Shi / Ruth Hüttenhain / Sergi Ferré / Eugene Kiyatkin / Jordi Bonaventura / Yavin Shaham / Venetia Zachariou / Michael H Baumann / Georgios Skiniotis / Kenner C Rice / Michael Michaelides /
PubMed AbstractDeveloping safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy ...Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction. Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling. Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR-galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.
External linksNature / PubMed:41922775
MethodsEM (single particle)
Resolution2.3 Å
Structure data

70071

9o36

EMDB-70071, PDB-9o36:
CryoEM structure of mu-opioid receptor - Gi protein complex bound to fluornitrazene (FNZ)
Method: EM (single particle) / Resolution: 2.3 Å

Chemicals

PDB-1b79:
N-TERMINAL DOMAIN OF DNA REPLICATION PROTEIN DNAB

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Complex / Receptor / Agonist / MOR

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