Discovery of Novel pH-Sensitive μ‑OpioidReceptor 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 <b>22</b> showed high pH sensitivity for MOR with a <i>K</i>_{i pH 7.4}/<i>K</i>_{i pH 6.4} ratio of 6.6. Compound <b>22</b> acted as an MOR agonist in the functional test. Compound <b>22</b> 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 <b>22</b> showed reduced side effects when compared to the equianalgesic dose of fentanyl, including physical dependence, hyperlocomotion, and constipation. Compound <b>22</b> holds promise as a safe candidate for further development as an analgesic with diminished side effects.