Enhancing inactivation rather than reducing activation of Nav1.7 channels by a clinically effective analgesic CNV1014802
文献类型：期刊论文
| 作者 | Zheng, Yue-ming2; Wang, Wan-fu2,3; Li, Yan-fen2,4; Yu, Yong1; Gao, Zhao-bing2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2018-04 |
| 卷号 | 39期号:4页码:587-596 |
| 关键词 | Nav1.7 channels analgesics CNV1014802 inactivated state paroxysmal extreme pain disorder |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2017.151 |
| 文献子类 | Article |
| 英文摘要 | The Nav1.7 channel represents a promising target for pain relief. In the recent decades, a number of Nav1.7 channel inhibitors have been developed. According to the effects on channel kinetics, these inhibitors could be divided into two major classes: reducing activation or enhancing inactivation. To date, however, only several inhibitors have moved forward into phase 2 clinical trials and most of them display a less than ideal analgesic efficacy, thus intensifying the controversy regarding if an ideal candidate should preferentially affect the activation or inactivation state. In the present study, we investigated the action mechanisms of a recently clinically confirmed inhibitor CNV1014802 using both electrophysiology and site-directed mutagenesis. We found that CNV1014802 inhibited Nav1.7 channels through stabilizing a nonconductive inactivated state. When the cells expressing Nav1.7 channels were hold at 70 mV or 120 mV, the half maximal inhibitory concentration (IC50) values (with 95% confidence limits) were 1.77 (1.20-2.33) and 71.66 (46.85-96.48) mu mol/L, respectively. This drug caused dramatic hyperpolarizing shift of channel inactivation but did not affect activation. Moreover, CNV1014802 accelerated the onset of inactivation and delayed the recovery from inactivation. Notably, application of CNV1014802 (30 mu mol/L) could rescue the Nav1.7 mutations expressed in CHO cells that cause paroxysmal extreme pain disorder (PEPD), thereby restoring the impaired inactivation to those of the wild-type channel. Our study demonstrates that CNV1014802 enhances the inactivation but does not reduce the activation of Nav1.7 channels, suggesting that identifying inhibitors that preferentially affect inactivation is a promising approach for developing drugs targeting Nav1.7. |
| WOS关键词 | VOLTAGE-GATED SODIUM ; EXTREME PAIN DISORDER ; NA(V)1.7 MUTATION ; ALPHA-SUBUNIT ; ERYTHROMELALGIA ; CARBAMAZEPINE ; FAMILY ; SCN9A ; INHIBITION ; LIDOCAINE |
| 资助项目 | China's Post-Doctoral Science Fund[2016M591728] ; National Key Scientific Instrument & Equipment Development Program of China[2012YQ03026010] ; National Natural Science Foundation of China[61327014] ; National Natural Science Foundation of China[61175103] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:6201261 |
| WOS记录号 | WOS:000429013200010 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279831]  |
| 专题 | 神经药理学研究国际科学家工作站 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Yu, Yong; Gao, Zhao-bing |
| 作者单位 | 1.Fudan Univ, Zhongshan Hosp, Dept Neurosurg, Shanghai 200032, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 4.Shanghai Univ, Sch Life Sci, Shanghai Key Lab Bioenergy Crops, Shanghai 200444, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zheng, Yue-ming,Wang, Wan-fu,Li, Yan-fen,et al. Enhancing inactivation rather than reducing activation of Nav1.7 channels by a clinically effective analgesic CNV1014802[J]. ACTA PHARMACOLOGICA SINICA,2018,39(4):587-596. |
| APA | Zheng, Yue-ming,Wang, Wan-fu,Li, Yan-fen,Yu, Yong,&Gao, Zhao-bing.(2018).Enhancing inactivation rather than reducing activation of Nav1.7 channels by a clinically effective analgesic CNV1014802.ACTA PHARMACOLOGICA SINICA,39(4),587-596. |
| MLA | Zheng, Yue-ming,et al."Enhancing inactivation rather than reducing activation of Nav1.7 channels by a clinically effective analgesic CNV1014802".ACTA PHARMACOLOGICA SINICA 39.4(2018):587-596. |
入库方式： OAI收割
来源：上海药物研究所
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