Article

Enhancing inactivation rather than reducing activation of Nav1.7 channels by a clinically effective analgesic CNV1014802

Authors: Yue-ming ZHENG1, Wan-fu WANG1,2, Yan-fen LI1,3, Yong YU4, Zhao-bing GAO1
1 CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
3 Shanghai Key Laboratory of Bio-Energy Crops, School of Life Sciences, Shanghai University, Shanghai 200444, China
4 Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Corresponding to: Yong YU: yu.yong@zs-hospital.sh.cn, Zhao-bing GAO: zbgao@simm.ac.cn,
DOI: 10.1038/aps.2017.151
Received: 2 November 2017
Accepted: 19 July 2017
Advance online: 3 September 2017

Abstract

Abstract
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) μmol/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 μmol/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.
Keywords: Nav1.7 channels; analgesics; CNV1014802; inactivated state; paroxysmal extreme pain disorder