Discovery of novel dual μOR/σ1R ligands as potent analgesics with reduced tolerance liability and improved safety profiles.

Opioid tolerance remains a widespread challenge in pain management, as prolonged μOR activation progressively diminishes analgesic efficacy, necessitating dose escalation and thereby increasing the risk of adverse effects. σ1R antagonism has been shown to potentiate opioid antinociception and mitigate the development of opioid tolerance. However, whether these complementary pharmacological actions can be effectively integrated into a single dual-target ligand remains underexplored. Our previous work yielded 4x, a promising dual μOR agonist/σ1R antagonist with potent in vitro and in vivo activities, yet significant hERG inhibition impeded its further development. Herein, we performed rational drug design and structural modifications, leading to the discovery of compounds 10q and 13d. These two compounds not only retained potent μOR agonism and σ1R antagonism but also exhibited markedly reduced hERG inhibition, substantially widening the therapeutic window. Furthermore, 10q and 13d showed favorable safety profiles, desirable pharmacokinetic properties, and markedly attenuated tolerance liability in vivo, collectively positioning them as advanced leads. These findings validate the dual-target strategy as a viable approach to decouple potent antinociception from tolerance escalation, and provide a chemical foundation for developing safer opioid analgesics.