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Scientists discovered a hidden CB₁ receptor pocket and engineered a drug to exploit it, offering the promise of safer, more targeted treatments for chronic pain.

According to a study published in Nature, researchers have uncovered a previously concealed binding site on the type 1 cannabinoid receptor (CB₁)—a pivotal component of the endocannabinoid system that regulates both central nervous system (CNS) and peripheral functions—and have engineered a drug to exploit this site. This breakthrough not only offers the promise of safer, more targeted treatments for chronic pain but also establishes a new strategy for designing receptor‐specific drugs across a vast family of therapeutic targets.

“The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain,” observed study author Vipin Ashok Rangari, PhD, of Washington University in St. Louis, and colleagues. “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.”

Computational Design of Positively Charged Ligands

Leveraging the potent CB₁ agonist MDMB-Fubinaca, the team synthesized positively charged derivatives predicted to remain confined to peripheral tissues. According to the study, molecular dynamics simulations uncovered a rarely accessible “cryptic” pocket adjacent to the conserved signaling residue D²^.⁵⁰. The team stated that by targeting this pocket, they hypothesized a shift toward G-protein signaling with reduced arrestin recruitment.

Structural Confirmation & Biased Signaling

According to the study, high-resolution crystallography confirmed that the designed ligands penetrate the cryptic pocket, stabilizing CB₁ in a conformation incompatible with arrestin engagement. Subsequent pharmacologic assays confirmed a pronounced bias toward G-protein–mediated pathways, effectively decoupling receptor activation from arrestin-dependent internalization and downstream tolerance mechanisms.

VIP36: A Lead Compound with Peripheral Selectivity

The researchers reported that the lead candidate, VIP36, displayed negligible CNS penetration, ensuring peripheral restriction. In murine models of thermal nociception, inflammatory pain, and neuropathic pain, VIP36 achieved potent analgesia at doses 100-fold lower than those required to elicit central side effects. Crucially, repeated administration did not provoke significant tolerance, underscoring the therapeutic advantage of minimized arrestin recruitment.

Implications for Drug Development

“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,” the authors concluded. “This has substantial implications for chronic pain treatment but could also revolutionize the design of drugs targeting other G-protein-coupled receptors.”