%0 Journal Article
%T Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.
%A Shen S
%A Wu C
%A Lin G
%A Yang X
%A Zhou Y
%A Zhao C
%A Miao Z
%A Tian X
%A Wang K
%A Yang Z
%A Liu Z
%A Guo N
%A Li Y
%A Xia A
%A Zhou P
%A Liu J
%A Yan W
%A Ke B
%A Yang S
%A Shao Z
%J Proc Natl Acad Sci U S A
%V 121
%N 24
%D 2024 Jun 11
%M 38830102
%F 12.779
%R 10.1073/pnas.2321532121
%X Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and β-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.