Benzylpiperidine derivatives as new dual μ-opioid and σ₁ receptor ligands with potent antinociceptive effects

Dual-acting μ-opioid receptor (MOR)/sigma-1 receptor (σ₁R) 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 σ₁R ligands. The obtained benzylpiperidine analogs were tested for MOR and σ₁R binding affinity in vitro. The best compound 52 showed high affinity for both MOR [K_i (MOR) = 56.4 nM] and σ₁R [K_i (σ₁R) = 11.0 nM] and produced potent antinociceptive effects in the abdominal contraction test (ED₅₀ = 4.04 mg/kg in mice), carrageenan-induced inflammatory pain model (ED₅₀ = 6.88 mg/kg in mice), formalin test (ED₅₀ = 13.98 mg/kg in rats) and complete Freund's adjuvant (CFA)-induced chronic pain model (ED₅₀ = 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.