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Nature
Apr, 2025;640 (8057): 265-273.

A cryptic pocket in CB1 drives peripheral and functional selectivity.

Vipin Ashok Rangari, Evan S O'Brien, Alexander S Powers, Richard A Slivicki, Zachariah Bertels, Kevin Appourchaux, Deniz Aydin, Nokomis Ramos-Gonzalez, Juliet Mwirigi, Li Lin, Elizaveta Mangutov, Briana L Sobecks, Yaseen Awad-Agbaria, Manoj B Uphade, Jhoan Aguilar, Teja Nikhil Peddada, Yuki Shiimura, Xi-Ping Huang, Jakayla Folarin-Hines, Maria Payne, Anirudh Kalathil, Balazs R Varga, Brian K Kobilka, Amynah A Pradhan, Michael D Cameron, Kaavya Krishna Kumar, Ron O Dror, Robert W Gereau, Susruta Majumdar
Author Information
  1. Vipin Ashok Rangari: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. ORCID
  2. Evan S O'Brien: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. ORCID
  3. Alexander S Powers: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  4. Richard A Slivicki: Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA. ORCID
  5. Zachariah Bertels: Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA.
  6. Kevin Appourchaux: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. ORCID
  7. Deniz Aydin: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. ORCID
  8. Nokomis Ramos-Gonzalez: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. ORCID
  9. Juliet Mwirigi: Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA. ORCID
  10. Li Lin: Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL, USA.
  11. Elizaveta Mangutov: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA.
  12. Briana L Sobecks: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  13. Yaseen Awad-Agbaria: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA.
  14. Manoj B Uphade: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA.
  15. Jhoan Aguilar: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA.
  16. Teja Nikhil Peddada: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  17. Yuki Shiimura: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  18. Xi-Ping Huang: Department of Pharmacology School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ORCID
  19. Jakayla Folarin-Hines: Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA.
  20. Maria Payne: Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA.
  21. Anirudh Kalathil: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA.
  22. Balazs R Varga: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA.
  23. Brian K Kobilka: Department of Computer Science, Stanford University, Stanford, CA, USA. ORCID
  24. Amynah A Pradhan: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. ORCID
  25. Michael D Cameron: Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL, USA. ORCID
  26. Kaavya Krishna Kumar: Department of Computer Science, Stanford University, Stanford, CA, USA. kaavyak@stanford.edu. ORCID
  27. Ron O Dror: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. ron.dror@stanford.edu. ORCID
  28. Robert W Gereau: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. gereaur@wustl.edu. ORCID
  29. Susruta Majumdar: Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. susrutam@email.wustl.edu. ORCID
PMID: 40044849 DOI: 10.1038/s41586-025-08618-7

Abstract

The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain. Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for pain relief, but its clinical use has been limited by centrally mediated psychoactivity and tolerance. We overcame both issues by designing peripherally restricted CB1 agonists that minimize arrestin recruitment. We achieved these goals by computationally designing positively charged derivatives of the potent CB1 agonist MDMB-Fubinaca. We designed these ligands to occupy a cryptic pocket identified through molecular dynamics simulations-an extended binding pocket that opens rarely and leads to the conserved signalling residue D (ref. ). We used structure determination, pharmacological assays and molecular dynamics simulations to verify the binding modes of these ligands and to determine the molecular mechanism by which they achieve this dampening of arrestin recruitment. Our lead ligand, VIP36, is highly peripherally restricted and demonstrates notable efficacy in three mouse pain models, with 100-fold dose separation between analgesic efficacy and centrally mediated side effects. VIP36 exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance. These results show how targeting a cryptic pocket in a G-protein-coupled receptor can lead to enhanced peripheral selectivity, biased signalling, desired in vivo pharmacology and reduced adverse effects. This has substantial implications for chronic pain treatment but could also revolutionize the design of drugs targeting other G-protein-coupled receptors.

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Grants

  1. F32 DA051160/NIDA NIH HHS
  2. K99 DA056691/NIDA NIH HHS
  3. R34 NS126036/NINDS NIH HHS

MeSH Term

Receptor, Cannabinoid, CB1
Animals
Mice
Molecular Dynamics Simulation
Ligands
Male
Humans
Binding Sites
Female
Analgesics
Drug Design
Drug Tolerance
Pain
Arrestin
Arrestins
Disease Models, Animal
Mice, Inbred C57BL

Chemicals

Receptor, Cannabinoid, CB1
Ligands
Analgesics
Arrestin
Arrestins
Journal Article
Article has an altmetric score of 763

Word Cloud

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