Structure-guided design of partial agonists at an opioid receptor

Balazs R. Varga, Sarah M. Bernhard, Amal El Daibani, Saheem A. Zaidi, Jordy H. Lam, Jhoan Aguilar, Kevin Appourchaux, Antonina L. Nazarova, Alexa Kouvelis, Ryosuke Shinouchi, Haylee R. Hammond, Shainnel O. Eans, Violetta Weinreb, Elyssa B. Margolis, Jonathan F. Fay, Xi-Ping Huang, Amynah Pradhan, Vsevolod Katritch (), Jay P. McLaughlin (), Susruta Majumdar () and Tao Che ()
Additional contact information
Balazs R. Varga: Washington University School of Medicine
Sarah M. Bernhard: Washington University School of Medicine
Amal El Daibani: Washington University School of Medicine
Saheem A. Zaidi: University of Southern California
Jordy H. Lam: University of Southern California
Jhoan Aguilar: Washington University School of Medicine
Kevin Appourchaux: Washington University School of Medicine
Antonina L. Nazarova: University of Southern California
Alexa Kouvelis: Washington University School of Medicine
Ryosuke Shinouchi: University of Florida
Haylee R. Hammond: University of Florida
Shainnel O. Eans: University of Florida
Violetta Weinreb: University of North Carolina Chapel Hill
Elyssa B. Margolis: University of California
Jonathan F. Fay: University of Maryland Baltimore
Xi-Ping Huang: University of North Carolina Chapel Hill
Amynah Pradhan: Washington University School of Medicine
Vsevolod Katritch: University of Southern California
Jay P. McLaughlin: University of Florida
Susruta Majumdar: Washington University School of Medicine
Tao Che: Washington University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ opioid receptor (δOR) is a promising target, as it lacks the respiratory depression associated with µ opioid receptor (µOR) agonists. However, early δOR full agonists caused seizures, limiting their clinical use. Partial δOR agonists may offer more controlled receptor activation than full agonists, but their development has been hindered by uncertainty regarding the molecular mechanism of partial agonism. Here we show that C6-Quino, a bitopic ligand developed through structure-based design, acts as a selective δOR partial agonist. Functional studies reveal that C6-Quino shows differential activity at G-protein and arrestin pathways and interacts with the sodium binding pocket, confirmed through cryo-EM analysis. C6-Quino demonstrates oral activity, analgesic activity in chronic pain models without causing δOR-related seizures and µOR-related adverse effects which have limited opioid usage in recent times. This discovery outlines a new strategy for developing δOR-targeted analgesics and provides a framework for optimizing signaling profiles of other Class A GPCRs.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-57734-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57734-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-57734-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().