A µ-opioid receptor superagonist analgesic with minimal adverse effects
. 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.
Authors
- Sergi Ferré (ORCID: https://orcid.org/0000-0002-1747-1779)
- Tongzhen Xie (ORCID: https://orcid.org/0000-0002-0968-0079)
- Reece C. Budinich
- Emilya Ventriglia (ORCID: https://orcid.org/0000-0001-5077-5443)
- Jennifer M. Bossert (ORCID: https://orcid.org/0000-0001-5636-4071)
- Ilinca M. Giosan
- Garrett Enten (ORCID: https://orcid.org/0000-0002-9012-0246)
- M. Sacco (ORCID: https://orcid.org/0000-0001-5930-7363)
- Zachary J. Frangos (ORCID: https://orcid.org/0000-0002-5499-4050)
- Óscar Solís (ORCID: https://orcid.org/0000-0002-8285-5891)
- Robert F. Dannals (ORCID: https://orcid.org/0000-0002-5483-5914)
- Eugene A. Kiyatkin (ORCID: https://orcid.org/0000-0002-3744-0873)
- Angelina A. Mullarkey
- Dain R. Brademan (ORCID: https://orcid.org/0000-0002-0971-9711)
- Shinbe Choi (ORCID: https://orcid.org/0009-0006-3505-4318)
- Jordi Bonaventura (ORCID: https://orcid.org/0000-0002-4745-0151)
- Grant C. Glatfelter (ORCID: https://orcid.org/0000-0003-1011-9083)
- G Skiniotis
- Kiera E. Caldwell
- Agnieszka Sulima (ORCID: https://orcid.org/0000-0002-8849-9736)
- Daniel P. Holt
- Michael J. Robertson (ORCID: https://orcid.org/0000-0003-2610-680X)
- W. Michael Dunne
- Ruth Hüttenhain (ORCID: https://orcid.org/0000-0002-0896-5910)
- Rana Rais (ORCID: https://orcid.org/0000-0003-4059-2453)
- Venetia Zachariou (ORCID: https://orcid.org/0000-0003-3194-8569)
- Zelai Garçon-Poca
- Amelie Essmann (ORCID: https://orcid.org/0009-0008-9972-8187)
- Hannah Bonbrest
- Michael R. Noya
- César Quiroz
- K.C. Rice
- Feonil G. Limiac (ORCID: https://orcid.org/0009-0000-5180-8948)
- Ingrid Schoenborn
- Chae Bin Lee
- Ali Arce
- Li Chen
- Margaret Robinson
- Yavin Shaham
- Michael Michaelides
- Anna E. Tischer
- Michael H. Baumann
Institutions
- Boston University (US)
- St. Jude Children's Research Hospital (US)
- National Institute on Drug Abuse (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Bellvitge University Hospital (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Ajuntament de L’Hospitalet (ES)
- Universitat de Barcelona (ES)
- Stanford University (US)
Publication Details
- Journal
- Nature
- Published
- 2026-04-01
- DOI
- https://doi.org/10.1038/s41586-026-10299-9
- Citations
- 3
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 36.02