Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ₁R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ₁R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ₁R and MOR and good selectivity to additional receptors related to pain. Compound 114 showed powerful dose-dependent analgesic effects in the acetic acid writhing test, formalin test, hot plate test, and chronic constriction injury (CCI) neuropathic pain model. In contrast to an equianalgesic dose of fentanyl, compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence, and sedation. Lastly, the pharmacokinetic properties of this drug were also acceptable, and these results suggest that compound 114, as a mixed σ₁R/MOR ligand, has potential for treating neuropathic pain.

在这里，我们描述了一系列新的双功能哌啶酰胺衍生物作为 sigma-1 受体 (σ ₁ R) 拮抗剂和 mu 阿片受体 (MOR) 激动剂的优化、合成和相关的药理镇痛活性。_{在 σ 1} R 和 MOR 结合试验中对新化合物进行了体外评估。最有前途的化合物114（也称为HKC-126）显示出对 σ ₁ R 和 MOR 的优异亲和力以及对与疼痛相关的其他受体的良好选择性。化合物114在醋酸扭体试验、福尔马林试验、热板试验和慢性缩窄性损伤 (CCI) 神经性疼痛模型中显示出强大的剂量依赖性镇痛作用。与等镇痛剂量的芬太尼相比，化合物114产生的类阿片样副作用较少，例如奖赏责任、呼吸抑制、身体依赖和镇静作用。最后，该药物的药代动力学特性也是可以接受的，这些结果表明化合物114作为混合 σ ₁ R/MOR 配体，具有治疗神经性疼痛的潜力。