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 () and Susruta Majumdar ()
Additional contact information
Vipin Ashok Rangari: University of Health Sciences and Pharmacy and Washington University School of Medicine
Evan S. O’Brien: Stanford University School of Medicine
Alexander S. Powers: Stanford University School of Medicine
Richard A. Slivicki: Washington University School of Medicine
Zachariah Bertels: Washington University School of Medicine
Kevin Appourchaux: University of Health Sciences and Pharmacy and Washington University School of Medicine
Deniz Aydin: Stanford University School of Medicine
Nokomis Ramos-Gonzalez: University of Health Sciences and Pharmacy and Washington University School of Medicine
Juliet Mwirigi: Washington University School of Medicine
Li Lin: UF Scripps Biomedical Research
Elizaveta Mangutov: University of Health Sciences and Pharmacy and Washington University School of Medicine
Briana L. Sobecks: Stanford University School of Medicine
Yaseen Awad-Agbaria: University of Health Sciences and Pharmacy and Washington University School of Medicine
Manoj B. Uphade: University of Health Sciences and Pharmacy and Washington University School of Medicine
Jhoan Aguilar: University of Health Sciences and Pharmacy and Washington University School of Medicine
Teja Nikhil Peddada: Stanford University School of Medicine
Yuki Shiimura: Stanford University School of Medicine
Xi-Ping Huang: University of North Carolina at Chapel Hill
Jakayla Folarin-Hines: Washington University School of Medicine
Maria Payne: Washington University School of Medicine
Anirudh Kalathil: University of Health Sciences and Pharmacy and Washington University School of Medicine
Balazs R. Varga: University of Health Sciences and Pharmacy and Washington University School of Medicine
Brian K. Kobilka: Stanford University
Amynah A. Pradhan: University of Health Sciences and Pharmacy and Washington University School of Medicine
Michael D. Cameron: UF Scripps Biomedical Research
Kaavya Krishna Kumar: Stanford University
Ron O. Dror: Stanford University School of Medicine
Robert W. Gereau: University of Health Sciences and Pharmacy and Washington University School of Medicine
Susruta Majumdar: University of Health Sciences and Pharmacy and Washington University School of Medicine

Nature, 2025, vol. 640, issue 8057, 265-273

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-08618-7

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