发现一种新型 K7.2/7.3 通道激动剂，可用于治疗神经性疼痛。
Discovery of a novel K7.2/7.3 channels agonist for the treatment of neuropathic pain.
机构信息
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.
Medicine Center, Guangxi University of Science and Technology, Liuzhou, Guangxi, 545006, China.
出版信息
Eur J Med Chem. 2024 Dec 15;280:116953. doi: 10.1016/j.ejmech.2024.116953. Epub 2024 Oct 12.
Here, we designed, synthesized and evaluated a series of compounds as K7.2/7.3 channels (or KCNQ2/3) agonists. The new compounds were assayed in vitro for KCNQ2/3 and other receptors binding affinity. The desired compound 16 showed high activity for KCNQ2/3 (EC = 1.03 ± 0.07 μM) without acute liver injury compared to flupirtine. It demonstrated powerful dose-dependent effects in multiple analgesic models, such as chronic constriction injury (CCI, ED = 12.02 mg/kg) and streptozotocin-induced diabetic peripheral neuropathic pain (DPNP, ED = 9.63 mg/kg) models. Additionally, compound 16 showed low affinity for human ether-a-go-go-related gene (hERG), high thresholds for acute toxicity, good motor performance in the rotarod test and acceptable pharmacokinetic properties. These results suggest the potentiality of compound 16 for the treatment of neuropathic pain.
在这里，我们设计、合成并评估了一系列作为 K7.2/7.3 通道（或 KCNQ2/3）激动剂的化合物。新化合物在体外针对 KCNQ2/3 和其他受体的结合亲和力进行了测定。与氟吡汀相比，目标化合物 16 对 KCNQ2/3 具有高活性（EC=1.03±0.07μM），且无急性肝损伤。它在多种镇痛模型中表现出强大的剂量依赖性作用，例如慢性缩窄性损伤（CCI，ED=12.02mg/kg）和链脲佐菌素诱导的糖尿病周围神经病理性疼痛（DPNP，ED=9.63mg/kg）模型。此外，化合物 16 对人 Ether-a-go-go 相关基因（hERG）的亲和力低，急性毒性阈值高，在旋转棒试验中运动性能良好，药代动力学特性可接受。这些结果表明化合物 16 具有治疗神经病理性疼痛的潜力。
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