Discovery of a novel KV7.2/7.3 channels agonist for the treatment of neuropathic pain

  • Eur J Med Chem. 2024 Oct 12:280:116953. doi: 10.1016/j.ejmech.2024.116953.
Kun Qian  1 ,  Jingyan Zhou  1 ,  Jiaying Xiong  2 ,  Qing Wang  1 ,  Ling Chen  1 ,  Tao Zhuang  1 ,  Jian Jin  1 ,  Guisen Zhang  1 ,  Chao Hao  3 ,  Ling Huang  4 ,  Yin Chen  5
Affiliations
  • 1. 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.
  • 2. Medicine Center, Guangxi University of Science and Technology, Liuzhou, Guangxi, 545006, China.
  • 3. 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: [email protected].
  • 4. Grand Medical Nutrition Science (Wuhan) Co., LTD., Wuhan, 430040, China. Electronic address: [email protected].
  • 5. 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: [email protected].
PMID: 39406116 DOI: 10.1016/j.ejmech.2024.116953
Abstract

Here, we designed, synthesized and evaluated a series of compounds as KV7.2/7.3 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 (EC50 = 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, ED50 = 12.02 mg/kg) and streptozotocin-induced diabetic peripheral neuropathic pain (DPNP, ED50 = 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.

Keywords
Acute liver injury; Analgesic; Flupirtine; KCNQ2/3; Neuropathic pain.
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