PXD062863-1

PXD062863 is an original dataset announced via ProteomeXchange.

Title	A mu opioid receptor superagonist that produces analgesia with minimal adverse effects
Description	Developing safe and effective pain medications is an ongoing challenge for human health. Mu opioid receptor (MOR) agonists are essential pain medications, but their high intrinsic efficacy induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal, and addiction. Strategies to limit such effects traditionally include developing MOR agonists that have low intrinsic efficacy or preferentially activate G protein over β-arrestin signaling. We report the discovery of a novel MOR superagonist with supraphysiological intrinsic efficacy and a unique pharmacological profile that produces effective analgesia in rodents with minimal adverse side effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called Nitazenes. DFNZ has a unique spatiotemporal MOR cellular signaling profile that favors G protein activation over β-arrestin recruitment, impaired brain penetrance, and diminished efficacy at the MOR-galanin 1 receptor (Gal1R) heteromer. DFNZ does not induce respiratory depression, tolerance, or MOR desensitization after repeated exposure. Compared to other MOR agonists, DFNZ does not increase dopamine transmission in nucleus accumbens and has weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights on MOR pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that MOR superagonists cannot constitute safe and effective therapeutics.
HostingRepository	PRIDE
AnnounceDate	2026-05-26
AnnouncementXML	Submission_2026-05-25_22:12:55.154.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dain Brademan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF HT

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-11 11:59:49	ID requested
⏵ 1	2026-05-25 22:12:56	announced

Gomez JL, Ventriglia EN, Frangos ZJ, Sulima A, Robertson MJ, Sacco MD, Budinich RC, Giosan IM, Xie T, Solis O, Tischer AE, Bossert JM, Caldwell KE, Bonbrest H, Essmann A, Gar, ç, on-Poca ZM, Choi S, Noya MR, Limiac F, Arce A, Glatfelter GC, Robinson M, Chen L, Mullarkey AA, Brademan DR, Enten G, Dunne W, Quiroz C, Schoenborn I, Lee CB, Rais R, Holt DP, Dannals RF, Shi L, H, ü, ttenhain R, Ferr, é S, Kiyatkin E, Bonaventura J, Shaham Y, Zachariou V, Baumann MH, Skiniotis G, Rice KC, Michaelides M, -opioid receptor superagonist analgesic with minimal adverse effects. Nature, 652(8112):1393-1404(2026) [pubmed]

10.1038/s41586-026-10299-9;

submitter keyword: MOR, APEX, Opioids

Ruth Huttenhain, PhD
contact affiliation	Department of Molecular & Cellular Physiology Stanford University School of Medicine
contact email	ruthh@stanford.edu
lab head
Dain Brademan
contact affiliation	Stanford School of Medicine Molecular and Cellular Physiology
contact email	brademan@stanford.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062863
     1. Label: PRIDE project
     2. Name: A mu opioid receptor superagonist that produces analgesia with minimal adverse effects