Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain.,European Journal of Medicinal Chemistry

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Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-14 , DOI: 10.1016/j.ejmech.2020.112144
Jiaying Xiong ₁ , Jian Jin ₂ , Lanchang Gao ₁ , Chao Hao ₁ , Xin Liu ₁ , Bi-Feng Liu ₁ , Yin Chen ₂ , Guisen Zhang ₃

Affiliation

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ1) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ1 and μ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ1 receptor (Ki σ1 = 1.86 nM) and μ receptor (Ki μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ1/μ receptor profiles, may be a potential candidate for treating neuropathic pain.

中文翻译：

哌啶丙酰胺作为有效 sigma-1 受体拮抗剂和 mu 阿片受体激动剂的支架，用于治疗神经性疼痛。

我们设计并合成了一系列新型哌啶丙酰胺衍生物作为有效的 sigma-1 (σ1) 受体拮抗剂和 mu (μ) 阿片受体激动剂，并通过结合测定在体外测量了它们对 σ1 和 μ 受体的亲和力。新化合物的基本骨架包含4-取代哌啶环和N-芳基丙酰胺。化合物 44，N-(2-(4-(4-氟苄基)哌啶-1-基)乙基)-N-(4-甲氧基-苯基)丙酰胺，对 σ1 受体表现出最高的亲和力 (Ki σ1 = 1.86 nM)和 μ 受体（Ki μ = 2.1 nM）。它在福尔马林试验中表现出有效的镇痛活性（ED50 = 15.1 ± 1.67 mg/kg），并且在 CCI 模型中具有与 S1RA（σ1 拮抗剂）相当的镇痛效果。因此，具有混合 σ1/μ 受体谱的化合物 44 可能是治疗神经性疼痛的潜在候选者。

更新日期：2020-02-20

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