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

   
@article{APS10884,
	author = {Qiao-qiao Wang and Long Wang and Wen-bo Zhang and Chun-ping Tang and Xue-qin Chen and Yue-ming Zheng and Sheng Yao and Zhao-bing Gao and Yang Ye},
	title = {Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel},
	journal = {Acta Pharmacologica Sinica},
	volume = {44},
	number = {9},
	year = {2023},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10884}
}