哌啶丙酰胺作为一种有效的 sigma-1 受体拮抗剂和μ阿片受体激动剂的骨架，用于治疗神经性疼痛。
Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain.
机构信息
Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
Jiangsu Key Laboratory of Marine Biological Resources and Environment, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
出版信息
Eur J Med Chem. 2020 Apr 1;191:112144. doi: 10.1016/j.ejmech.2020.112144. Epub 2020 Feb 14.
We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ 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 σ receptor (K σ = 1.86 nM) and μ receptor (K μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ/μ receptor profiles, may be a potential candidate for treating neuropathic pain.
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（σ）受体拮抗剂和μ（μ）阿片受体激动剂，并通过结合测定法在体外测量它们对 σ 和 μ 受体的亲和力。新化合物的基本骨架包含 4-取代的哌啶环和 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 σ 受体（K σ = 1.86 nM）和 μ 受体（K μ = 2.1 nM）表现出最高的亲和力。它在福马林测试中表现出很强的镇痛活性（ED = 15.1 ± 1.67 mg/kg），并且在 CCI 模型中与 S1RA（σ 拮抗剂）具有等效的镇痛作用。因此，具有混合 σ/μ 受体特征的化合物 44 可能是治疗神经性疼痛的潜在候选药物。
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