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TitleStructure-guided design of partial agonists at an opioid receptor.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 2518, Year 2025
Publish dateMar 13, 2025
AuthorsBalazs 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 / Tao Che /
PubMed AbstractChronic 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 ...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.
External linksNat Commun / PubMed:40082451 / PubMed Central
MethodsEM (single particle)
Resolution2.62 - 2.8 Å
Structure data

45581

9cgj

EMDB-45581, PDB-9cgj:
CryoEM structure of delta opioid receptor bound to G proteins and a partial agonist
Method: EM (single particle) / Resolution: 2.8 Å

45582

9cgk

EMDB-45582, PDB-9cgk:
CryoEM structure of delta opioid receptor bound to G proteins and a full bitopic agonist
Method: EM (single particle) / Resolution: 2.62 Å

Chemicals

PDB-1awc:
MOUSE GABP ALPHA/BETA DOMAIN BOUND TO DNA

PDB-1awd:
FERREDOXIN [2FE-2S] OXIDIZED FORM FROM CHLORELLA FUSCA

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / Delta OPIOID Receptor / bitopic ligand

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