Discovery of cyanoguanidine derivatives as biased μ-opioid receptor agonists

Opioid agonists, including morphine and its derivatives, have historically been utilized in conventional pain relief therapies. However, the morphine-like side effects associated with these compounds have constrained their broader application in clinical environments. Fortunately, novel compounds that selectively activate μ-opioid receptors (MOR) without activating the β-arrestin2 pathway, such as PZM21 and TRV130, demonstrate the potential to mitigate side effects while maintaining analgesic efficacy. In this study, we structurally modified PZM21 to get a series of compounds with a 2-cyanoguanidine scaffold, the majority of which display significant analgesic effects. Notably, Compound I-11 exhibited an analgesic effect comparable to that of morphine and selectively activates μ-opioid receptors while avoiding the activation of the β-arrestin2 pathway. Our work not only introduces a novel biased μ-opioid receptor agonist but also serves as a valuable reference for the further optimization of PZM21.