Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel PMID: 37142682

ADC Targets in Oncology

2026-04-10

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

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.

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 (V_1/2 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.