Structure-guided design of partial agonists at an opioid receptor
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57734-5 |
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| author | 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 Tao Che |
| author_facet | 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 Tao Che |
| author_sort | Balazs R. Varga |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-01277f7bd84242c98c41e0959f62fd74 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-01277f7bd84242c98c41e0959f62fd742025-08-20T03:02:19ZengNature PortfolioNature Communications2041-17232025-03-0116111510.1038/s41467-025-57734-5Structure-guided design of partial agonists at an opioid receptorBalazs R. Varga0Sarah M. Bernhard1Amal El Daibani2Saheem A. Zaidi3Jordy H. Lam4Jhoan Aguilar5Kevin Appourchaux6Antonina L. Nazarova7Alexa Kouvelis8Ryosuke Shinouchi9Haylee R. Hammond10Shainnel O. Eans11Violetta Weinreb12Elyssa B. Margolis13Jonathan F. Fay14Xi-Ping Huang15Amynah Pradhan16Vsevolod Katritch17Jay P. McLaughlin18Susruta Majumdar19Tao Che20Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineCenter for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineCenter for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineDepartment of Quantitative & Computational Biology and Department of Chemistry, University of Southern CaliforniaDepartment of Quantitative & Computational Biology and Department of Chemistry, University of Southern CaliforniaCenter for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineCenter for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineDepartment of Quantitative & Computational Biology and Department of Chemistry, University of Southern CaliforniaCenter for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineDepartment of Pharmacodynamics, University of FloridaDepartment of Pharmacodynamics, University of FloridaDepartment of Pharmacodynamics, University of FloridaDepartment of Pharmacology School of Medicine, University of North Carolina Chapel HillUCSF Weill Institute for Neurosciences, Department of Neurology, University of CaliforniaDepartment of Biochemistry and Molecular Biology, University of Maryland BaltimoreDepartment of Pharmacology School of Medicine, University of North Carolina Chapel HillCenter for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineDepartment of Quantitative & Computational Biology and Department of Chemistry, University of Southern CaliforniaDepartment of Pharmacodynamics, University of FloridaCenter for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineCenter for Clinical Pharmacology, Department of Anesthesiology, Washington University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-57734-5 |
| spellingShingle | 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 Tao Che Structure-guided design of partial agonists at an opioid receptor Nature Communications |
| title | Structure-guided design of partial agonists at an opioid receptor |
| title_full | Structure-guided design of partial agonists at an opioid receptor |
| title_fullStr | Structure-guided design of partial agonists at an opioid receptor |
| title_full_unstemmed | Structure-guided design of partial agonists at an opioid receptor |
| title_short | Structure-guided design of partial agonists at an opioid receptor |
| title_sort | structure guided design of partial agonists at an opioid receptor |
| url | https://doi.org/10.1038/s41467-025-57734-5 |
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