2. Academic Validation
  3. A cryptic pocket in CB1 drives peripheral and functional selectivity

A cryptic pocket in CB1 drives peripheral and functional selectivity

  • Nature. 2025 Apr;640(8057):265-273. doi: 10.1038/s41586-025-08618-7.
Vipin Ashok Rangari # 1 2,  Evan S O'Brien # 3 4,  Alexander S Powers # 3 5 6 7,  Richard A Slivicki # 2,  Zachariah Bertels # 2,  Kevin Appourchaux 1 2,  Deniz Aydin 3 5 6 7,  Nokomis Ramos-Gonzalez 1 2,  Juliet Mwirigi 2,  Li Lin 8,  Elizaveta Mangutov 1 2,  Briana L Sobecks 3 5 6 7,  Yaseen Awad-Agbaria 1 2,  Manoj B Uphade 1 2,  Jhoan Aguilar 1 2,  Teja Nikhil Peddada 3,  Yuki Shiimura 3 9,  Xi-Ping Huang 10,  Jakayla Folarin-Hines 2,  Maria Payne 2,  Anirudh Kalathil 1,  Balazs R Varga 1 2,  Brian K Kobilka 5,  Amynah A Pradhan 1 2,  Michael D Cameron 8,  Kaavya Krishna Kumar 11,  Ron O Dror 12 13 14 15,  Robert W Gereau 4th 16 17,  Susruta Majumdar 18 19
Affiliations

Affiliations

  • 1 Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA.
  • 2 Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA.
  • 3 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  • 4 Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5 Department of Computer Science, Stanford University, Stanford, CA, USA.
  • 6 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 7 Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
  • 8 Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL, USA.
  • 9 Division of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, Japan.
  • 10 Department of Pharmacology School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 11 Department of Computer Science, Stanford University, Stanford, CA, USA. kaavyak@stanford.edu.
  • 12 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. ron.dror@stanford.edu.
  • 13 Department of Computer Science, Stanford University, Stanford, CA, USA. ron.dror@stanford.edu.
  • 14 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. ron.dror@stanford.edu.
  • 15 Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA. ron.dror@stanford.edu.
  • 16 Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. gereaur@wustl.edu.
  • 17 Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA. gereaur@wustl.edu.
  • 18 Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St. Louis, MO, USA. susrutam@email.wustl.edu.
  • 19 Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA. susrutam@email.wustl.edu.
  • # Contributed equally.
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 pain1. 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-Fubinaca2. 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 D2.50 (ref. 3). 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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