{Reference Type}: Journal Article
{Title}: Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.
{Author}: Shen S;Wu C;Lin G;Yang X;Zhou Y;Zhao C;Miao Z;Tian X;Wang K;Yang Z;Liu Z;Guo N;Li Y;Xia A;Zhou P;Liu J;Yan W;Ke B;Yang S;Shao Z;
{Journal}: Proc Natl Acad Sci U S A
{Volume}: 121
{Issue}: 24
{Year}: 2024 Jun 11
{Factor}: 12.779
{DOI}: 10.1073/pnas.2321532121
{Abstract}: 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.