Thiophenpiperazine amide derivatives as new dual MOR and σ1R ligands for the treatment of pain

Abstract

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the μ-opioid (MOR) and sigma-1 (σ₁R) receptors are reported. Compound 23 exhibited good affinity to σ₁R (K_i = 44.7 ± 7.05 nM) and high selectivity to σ₂R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED₅₀ = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED₅₀ = 5.23 mg/kg)). We obtained new dual ligands that might serve as starting points for preparing targeted tools. Furthermore, 23 may be a useful chemical probe for understanding more fully analgesic effects associated with MOR agonism and σ₁R antagonism.

Keywords: Analgesic effects; Dual MOR and σ(1)R ligands; MOR agonism and σ(1)R antagonism; Thiophenpiperazine amide derivatives.