Benzylpiperidine derivatives as new dual μ-opioid and σ receptor ligands with potent antinociceptive effects.

Dual-acting μ-opioid receptor (MOR)/sigma-1 receptor (σR) ligands have displayed promise in exerting robust antinociceptive effects while reducing opioid-related side effects. To discover safer and more effective analgesics, we designed, prepared, and evaluated 30 benzylpiperidine derivatives as dual MOR and σR ligands. The obtained benzylpiperidine analogs were tested for MOR and σR binding affinity in vitro. The best compound 52 showed high affinity for both MOR [K (MOR) = 56.4 nM] and σR [K (σR) = 11.0 nM] and produced potent antinociceptive effects in the abdominal contraction test (ED = 4.04 mg/kg in mice), carrageenan-induced inflammatory pain model (ED = 6.88 mg/kg in mice), formalin test (ED = 13.98 mg/kg in rats) and complete Freund's adjuvant (CFA)-induced chronic pain model (ED = 7.62 mg/kg in mice). Moreover, 52 had less MOR-related adverse effects than oxycodone, including constipation, acute hyperlocomotion and physical dependence. The above results suggested that 52 may be a promising candidate for the development of safer analgesics.