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A new series of thiophenpiperazine amide derivatives as potent dual ligands for the μ-opioid (MOR) and sigma-1 (σ 1 R) receptors are reported. Compound 23 exhibited good affinity to σ 1 R (K i = 44.7 ± 7.05 nM) and high selectivity to σ 2 R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED 50 = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED 50 = 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 σ 1 R antagonism. • A series of thiophenpiperazine amide derivatives were synthesised. • The structure activity relationships of the targeted compounds were summarised. • Selected compounds exhibited the desirable potent σ 1 R antagonism and MOR agonism profiles. • The most active compound exerted potent analgesic activity in in vivo animal model. [ABSTRACT FROM AUTHOR]