Inhibition of NaV1.7: the possibility of ideal analgesics

Abstract

The selective inhibition of Na_V1.7 is a promising strategy for developing novel analgesic agents with fewer adverse effects. Although the potent selective inhibition of Na_V1.7 has been recently achieved, multiple Na_V1.7 inhibitors failed in clinical development. In this review, the relationship between preclinical in vivo efficacy and Na_V1.7 coverage among three types of voltage-gated sodium channel (VGSC) inhibitors, namely conventional VGSC inhibitors, sulphonamides and acyl sulphonamides, is discussed. By demonstrating the PK/PD discrepancy of preclinical studies versus in vivo models and clinical results, the potential reasons behind the disconnect between preclinical results and clinical outcomes are discussed together with strategies for developing ideal analgesic agents.

Fig. 1. The structure of VGSC. A) The topology of VGSC pore-forming α subunit. There are six α-helices (S1–S6) in each domain (DI–DIV). Two helices (S5–S6) form the channel pore, and four helices (S1–S4) form a voltage sensor, in which positively charged residues present in each S4 contribute to the conformational change of VGSC via membrane voltage. B) Top view of hNa_V1.7 pore-forming α-subunit with its domains presented in a space-filling model. C) and D) Side and top views of hNa_V1.7 pore-forming α-subunit with its domains and binding sites presented in ribbon representation (PDB entry: 5EK0). Each domain is presented by the following colours: DI VSD (blue), DI PD (light blue), DII VSD (orange), DII PD (light orange), DIII VSD (yellow), DIII PD (light yellow), DIV VSD (green) and DIV PD (light green).

Fig. 2. Voltage-dependent conformational changes of VGSCs. A) Three distinct voltage-dependent conformational states: resting, open and inactivated states. B) An example of voltage protocol for an automated patch-clamp assay that permits evaluation of both resting (V_rest) and inactivated (V_1/2) states of hNa_V1.7.