Abstract

Two-pore potassium channels (K2Ps)
represent an underexplored and diverse family of 18 potassium channels, each
possessing a unique four-transmembrane-domain, two-pore structure. Recently
their characterisation and functional roles in carrying background potassium
current and maintaining cell resting membrane potential have begun to be
developed and described. Coupled with a growing body of genetic and functional
evidence for roles in migraine and pain, there is significant interest in the
potential of activating K2Ps as drug targets in these important areas. In many
cases there remains a need for selective small molecule activators
with which to further understand and probe structural, functional and
mechanistic aspects of these channels. By means of a target-class screening
approach, we have been actively involved in efforts to uncover such tool molecules
for several K2P channels. Here we will present property-based analyses of the
successful screening outputs, in the contexts of individual channels and across
the wider family, and show how these have enabled selection of appropriate
chemistries for further exploration.  In
addition, we will highlight our first examples of selective K2P activators and
some early structure activity relationships, which will help to deepen
understanding of how these channels function in disease biology.