Discovery of μ,δ-Opioid Receptor Dual-Biased Agonists That Overcome the Limitation of Prior Biased Agonists

[Image: see text] Morphine is widely used in pain management although the risk of side effects is significant. The use of biased agonists to the G protein of μ-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 previously biased agonist misidentification. Here, we have devised a strategy to discover biased agonists with intrinsic efficacy. We computationally simulated 430 000 molecular dockings to the μ-opioid receptor to construct a compound library. Hits were then verified experimentally. Using the verified compounds, we performed simulations to build a second library with a common scaffold and selected compounds that showed a bias to μ- and δ-opioid receptors in a cell-based assay. Three compounds (ID110460001, ID110460002, and ID110460003) with a dual-biased agonistic effect for μ- and δ-opioid receptors were identified. These candidates are full agonists for the μ-opioid receptor and show specific binding modes. On the basis of our findings, we expect our novel compounds to act as more biased agonists compared to existing drugs, including oliceridine.