Naphthylisoquinoline alkaloids,a new structural template inhibitor of Navl.7 sodium channel
文献类型：期刊论文
| 作者 | Wang Qiaoqiao2; Wang Long1; Zhang Wenbo1; Tang Chunping2 ; Chen Xueqin2; Zheng Yueming2; Yao Sheng2; Gao Zhaobing2; Ye Yang2
|
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2023 |
| 卷号 | 44期号:9页码:1768 |
| 关键词 | Navl.7 channel naphthylisoquinolines Ancistrocladus tectorius dorsal root ganglion neurons formalin-induced mouse inflammatory pain model analgesics |
| ISSN号 | 1671-4083 |
| 英文摘要 | Voltage-gated sodium channel 1.7 (Navl.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 Navl.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 Ka radiation. All the NIQs showed inhibitory activities against the Navl.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 IC_(50) 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 Navl.7 channel. In acutely isolated dorsal root ganglion (DRG) neurons, compound 2 (10μM) 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. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/307410]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 1.南京中医药大学 2.中国科学院上海药物研究所 |
| 推荐引用方式 GB/T 7714 | Wang Qiaoqiao,Wang Long,Zhang Wenbo,et al. Naphthylisoquinoline alkaloids,a new structural template inhibitor of Navl.7 sodium channel[J]. ACTA PHARMACOLOGICA SINICA,2023,44(9):1768. |
| APA | Wang Qiaoqiao.,Wang Long.,Zhang Wenbo.,Tang Chunping.,Chen Xueqin.,...&Ye Yang.(2023).Naphthylisoquinoline alkaloids,a new structural template inhibitor of Navl.7 sodium channel.ACTA PHARMACOLOGICA SINICA,44(9),1768. |
| MLA | Wang Qiaoqiao,et al."Naphthylisoquinoline alkaloids,a new structural template inhibitor of Navl.7 sodium channel".ACTA PHARMACOLOGICA SINICA 44.9(2023):1768. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。