Discovery of Novel pH-Sensitive μ-Opioid Receptor Agonists as Potent Analgesics with Reduced Side Effects.

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 22 showed high pH sensitivity for MOR with a K i pH 7.4/K i pH 6.4 ratio of 6.6. Compound 22 acted as an MOR agonist in the functional test. Compound 22 exhibited good antinociceptive effects in the acetic acid-induced writhing test (ED50 = 1.5 mg/kg) and carrageenan-induced inflammatory pain model (ED50 = 3.3 mg/kg) in mice. Moreover, compound 22 showed reduced side effects when compared to the equianalgesic dose of fentanyl, including physical dependence, hyperlocomotion, and constipation. Compound 22 holds promise as a safe candidate for further development as an analgesic with diminished side effects.