Structure-based discovery of cannabinoid analogs with reduced adverse effects

Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits; nevertheless, it is accompanied by adverse effects that impede its medical applications. The selective activation or inhibition of G-protein or β-arrestin signaling cascades could potentially generate drugs with a more precise targeting profile and fewer adverse effects, ultimately expanding the therapeutic range. However, the lack of understanding of the mechanism of β-arrestin-1 (βarr1) coupling and signaling bias has hindered drug development targeting CB1. Here, we present the high-resolution cryo-electron microscopy structure of CB1-βarr1 complex bound to the synthetic cannabinoid MDMB-Fubinaca (FUB), revealing notable differences in the transducer pocket and ligand-binding site compared with the Gi-protein complex. βarr1 occupies a wider transducer pocket promoting substantial outward movement of the TM6 and distinctive twin toggle switch rearrangements. FUB adopts a different pose, inserting more deeply than the Gi-coupled state, which enabled the design of the G-protein biased CB1 agonists that displayed analgesic effects in mice but without inducing tolerance and hypothermia. Taken together, our findings unravel the molecular mechanism of signaling bias toward CB1, facilitating the development of safe and effective cannabinoid analogs with reduced side effects.