2. Academic Validation
  3. A µ-opioid receptor superagonist analgesic with minimal adverse effects

A µ-opioid receptor superagonist analgesic with minimal adverse effects

  • Nature. 2026 Apr 1. doi: 10.1038/s41586-026-10299-9.
Juan L Gomez 1,  Emilya N Ventriglia 1,  Zachary J Frangos 1,  Agnieszka Sulima 2,  Michael J Robertson 3 4,  Michael D Sacco 3 4,  Reece C Budinich 1,  Ilinca M Giosan 5,  Tongzhen Xie 5,  Oscar Solis 1,  Anna E Tischer 1,  Jennifer M Bossert 6,  Kiera E Caldwell 6,  Hannah Bonbrest 6,  Amelie Essmann 7 8,  Zelai M Garçon-Poca 7 8,  Shinbe Choi 9,  Michael R Noya 9,  Feonil Limiac 9,  Ali Arce 9,  Grant C Glatfelter 10,  Margaret Robinson 11,  Li Chen 11,  Angelina A Mullarkey 3,  Dain R Brademan 3,  Garrett Enten 12,  William Dunne 1,  César Quiroz 12,  Ingrid Schoenborn 1,  Chae Bin Lee 13 14,  Rana Rais 13 14,  Daniel P Holt 15,  Robert F Dannals 15,  Lei Shi 11,  Ruth Hüttenhain 3,  Sergi Ferré 12,  Eugene Kiyatkin 9,  Jordi Bonaventura 7 8,  Yavin Shaham 6,  Venetia Zachariou 5,  Michael H Baumann 10,  Georgios Skiniotis 16 17 18 19,  Kenner C Rice 20,  Michael Michaelides 21
Affiliations

Affiliations

  • 1 Biobehavioral Imaging and Molecular Neuropsychopharmacology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
  • 2 Drug Design and Synthesis Section, Molecular Targets and Medication Discovery Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
  • 3 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  • 4 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
  • 6 Neurobiology of Relapse Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
  • 7 Departament de Patologia i Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain.
  • 8 Neuropharmacology and Pain Group, Neuroscience Program, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, Spain.
  • 9 Behavioral Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
  • 10 Designer Drug Research Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
  • 11 Computational Chemistry and Molecular Biophysics Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
  • 12 Integrative Neurobiology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA.
  • 13 Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 14 Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 15 Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • 16 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. georgios.skiniotis@stjude.org.
  • 17 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. georgios.skiniotis@stjude.org.
  • 18 Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA. georgios.skiniotis@stjude.org.
  • 19 Center of Excellence for Structural Cell Biology, St Jude Children's Research Hospital, Memphis, TN, USA. georgios.skiniotis@stjude.org.
  • 20 Drug Design and Synthesis Section, Molecular Targets and Medication Discovery Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA. kennerr@nida.nih.gov.
  • 21 Biobehavioral Imaging and Molecular Neuropsychopharmacology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA. mike.michaelides@nih.gov.
PMID: 41922775 DOI: 10.1038/s41586-026-10299-9
Abstract

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 addiction1-7. 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 signalling8. 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z