Addition of a single methyl group to a small molecule sodium channel inhibitor introduces a new mode of gating modulation.

ABSTRACT:

Background and purpose

Aryl sulfonamide Nav 1.3 or Nav 1.7 voltage-gated sodium (Nav ) channel inhibitors interact with the Domain 4 voltage sensor domain (D4 VSD). During studies to better understand the structure-activity relationship of this interaction, an additional mode of channel modulation, specifically slowing of inactivation, was revealed by addition of a single methyl moiety. The objective of the current study was to determine if these different modulatory effects are mediated by the same or distinct interactions with the channel.

Experimental approach

Electrophysiology and site-directed mutation were used to compare the effects of PF-06526290 and its desmethyl analogue PF-05661014 on Nav channel function.

Key results

PF-05661014 selectively inhibits Nav 1.

SUBMITTER: Wang L 

PROVIDER: S-EPMC4621986 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature