2. Academic Validation
  3. Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel

Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel

  • Acta Pharmacol Sin. 2023 Sep;44(9):1768-1776. doi: 10.1038/s41401-023-01084-9.
Qiao-Qiao Wang # 1 2 3 4,  Long Wang # 5 6,  Wen-Bo Zhang 5 6,  Chun-Ping Tang 1 2,  Xue-Qin Chen 1 6,  Yue-Ming Zheng 7 8 9,  Sheng Yao 10 11 12 13,  Zhao-Bing Gao 14 15 16 17 18,  Yang Ye 19 20 21
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 4 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
  • 6 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 9 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 11 Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 12 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 13 Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, China. [email protected].
  • 14 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 15 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 16 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China. [email protected].
  • 17 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 18 Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, China. [email protected].
  • 19 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 20 Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 21 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • # Contributed equally.
PMID: 37142682 DOI: 10.1038/s41401-023-01084-9
Abstract

Voltage-gated Sodium Channel 1.7 (Nav1.7) remains one of the most promising drug targets for pain relief. In the current study, we conducted a high-throughput screening of Natural Products in our in-house compound library to discover novel Nav1.7 inhibitors, then characterized their pharmacological properties. We identified 25 naphthylisoquinoline Alkaloids (NIQs) from Ancistrocladus tectorius to be a novel type of Nav1.7 channel inhibitors. Their stereostructures including the linkage modes of the naphthalene group at the isoquinoline core were revealed by a comprehensive analysis of HRESIMS, 1D, and 2D NMR spectra as well as ECD spectra and single-crystal X-ray diffraction analysis with Cu Kα radiation. All the NIQs showed inhibitory activities against the Nav1.7 channel stably expressed in HEK293 cells, and the naphthalene ring in the C-7 position displayed a more important role in the inhibitory activity than that in the C-5 site. Among the NIQs tested, compound 2 was the most potent with an IC50 of 0.73 ± 0.03 µM. We demonstrated that compound 2 (3 µM) caused dramatical shift of steady-state slow inactivation toward the hyperpolarizing direction (V1/2 values were changed from -39.54 ± 2.77 mV to -65.53 ± 4.39 mV, which might contribute to the inhibition of compound 2 against the Nav1.7 channel. In acutely isolated dorsal root ganglion (DRG) neurons, compound 2 (10 μM) dramatically suppressed native sodium currents and action potential firing. In the formalin-induced mouse inflammatory pain model, local intraplantar administration of compound 2 (2, 20, 200 nmol) dose-dependently attenuated the nociceptive behaviors. In summary, NIQs represent a new type of Nav1.7 channel inhibitors and may act as structural templates for the following analgesic drug development.

Keywords

Ancistrocladus tectorius; Nav1.7 channel; analgesics; dorsal root ganglion neurons; formalin-induced mouse inflammatory pain model; naphthylisoquinolines.

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