Discovery of μ,δ-Opioid receptor dual biased agonists that overcome the limitation of prior biased agonists
Morphine is widely used to manage pain in patients, although the risk of side effects is significant. The use of biased agonists to the G protein of -opioid receptors has been suggested as a potential solution, although Oliceridine and PZM21 have previously failed to demonstrate benefits in clinical studies. An amplification-induced confusion in the process of comparing G protein and beta-arrestin pathways may account for previous biased agonist mis-identification. Here, we have devised a strategy to discover biased agonists with intrinsic efficacy. We computationally simulated 430,000 molecular dockings to the -opioid receptor to construct a compound library. Hits were then verified by experiment. Using the verified compounds, we performed simulations to build a second library with a common scaffold, and selected compounds which show biased features to and {delta}-opioid receptors through a cell-based assay. Three compounds (ID110460001, ID110460002, and ID110460003) with a dual biased agonistic effect for and {delta}-opioid receptors were identified. These candidates are full agonists for the -opioid receptor, and they show specific binding modes. Based on our findings, we expect our novel compound to act as a biased agonist than conventional drugs such as Oliceridine.