Discovery of a novel K V 7.2/7.3 channels agonist for the treatment of neuropathic pain.

Autor: Qian K; 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., Zhou J; 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., Xiong J; Medicine Center, Guangxi University of Science and Technology, Liuzhou, Guangxi, 545006, China., Wang Q; 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., Chen L; 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., Zhuang T; 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., Jin J; 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., Zhang G; 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., Hao C; 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. Electronic address: 2022000085@jou.edu.cn., Huang L; Grand Medical Nutrition Science (Wuhan) Co., LTD., Wuhan, 430040, China. Electronic address: huangcjia@126.com., Chen Y; 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. Electronic address: 2019000015@jou.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Dec 15; Vol. 280, pp. 116953. Date of Electronic Publication: 2024 Oct 12.
DOI: 10.1016/j.ejmech.2024.116953
Abstrakt: Here, we designed, synthesized and evaluated a series of compounds as K V 7.2/7.3 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 50  = 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 50  = 12.02 mg/kg) and streptozotocin-induced diabetic peripheral neuropathic pain (DPNP, ED 50  = 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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