To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ₁ receptor (σ₁R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (K_i = 6.5 nΜ; EC₅₀ = 48.5 nΜ, E_max = 66.3%) and σ₁R antagonism (K_i = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED₅₀ = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED₅₀ = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED₅₀ = 0.30 mg/kg, in mice). The contributions of MOR and σ₁R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ₁R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects—including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion—than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ₁R ligands as a promising avenue for the development of potent and safe analgesics.

为了开发更安全、更有效的镇痛剂，我们设计、合成并评估了一系列新的苄基氨基芬太尼衍生物作为双功能 μ 阿片受体 (MOR) 和 σ ₁受体 (σ ₁ R) 配体。化合物68（Tao-191）在体外表现出理想的MOR激动作用（K i ₌  6.5 nM；EC ₅₀  = 48.5 nM，E _max  = 66.3%）和σ ₁ R拮抗作用（K _i  = 35.7 nM），并发挥强大的镇痛作用在腹部收缩试验（ED ₅₀  = 0.32 mg/kg，在小鼠中）、福尔马林诱导的疼痛试验（II 期，ED ₅₀  = 2.26 mg/kg，在大鼠中）和紫杉醇诱导的神经性疼痛模型（ED ₅₀ = 0.30 mg/kg，在小鼠中）。_{通过分别与 MOR 拮抗剂纳洛酮和 σ 1} R 激动剂 PRE-084联合给药，验证了MOR 和 σ ₁ R 对其镇痛作用的贡献。在等镇痛剂量下，与芬太尼相比，化合物 68 引起的 MOR 相关副作用更少，包括身体和心理依赖、呼吸抑制、便秘和急性过度运动。该结果为进一步探索双 MOR/σ ₁ R 配体的作用和安全性提供了理论基础，作为开发有效和安全镇痛剂的有希望的途径。