Structure-based identification of a G protein–biased allosteric modulator of cannabinoid receptor CB1

Abstract The opioid crisis and widespread demand for pain management have intensified the search for nonopioid analgesics, placing the CB1 receptor in the spotlight as a promising target for advanced analgesics. However, Δ9-tetrahydrocannabinol (THC) and synthetic alternatives, binding to the orthosteric site of CB1, can trigger adverse side effects such as dependence, catalepsy, hypothermia, and addiction, limiting their clinical utility. Given the potential role of CB1-mediated Gi protein signaling in pain management, designing biased agonist-allosteric modulators (ago-BAMs) capable of inducing