Although μ-opioid receptor (MOR) agonists are the most effective drugs for relieving acute pain, nonselective activation of MOR can also lead to serious side effects. There is an urgent need for novel analgesics that can selectively activate MOR under pathological conditions while avoiding side effects under normal physiological conditions. In this study, a series of pH-sensitive 4-propionamide piperidine derivatives were synthesized and evaluated for their MOR activities and antinociceptive effects. Among them, compound