Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors

J Gen Physiol. 2018 Aug 6;150(8):1215-1230. doi: 10.1085/jgp.201711942. Epub 2018 Jul 12.

Abstract

Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential-generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetulus
  • High-Throughput Screening Assays
  • Kinetics
  • Shaker Superfamily of Potassium Channels / drug effects*
  • Small Molecule Libraries
  • Sulfonamides / pharmacology*

Substances

  • Shaker Superfamily of Potassium Channels
  • Small Molecule Libraries
  • Sulfonamides