Drug Development in Channelopathies: Allosteric Modulation of Ligand-Gated and Voltage-Gated Ion Channels

Ion channels have been characterized
as promising drug targets
for treatment of numerous human diseases. Functions of ion channels
can be fine-tuned by allosteric modulators, which interact with channels
and modulate their activities by binding to sites spatially discrete
from those of orthosteric ligands. Positive and negative allosteric
modulators have presented a plethora of potential therapeutic advantages
over traditionally orthosteric agonists and antagonists in terms of
selectivity and safety. This thematic review highlights the discovery
of representative allosteric modulators for ligand-gated and voltage-gated
ion channels, discussing in particular their identifications, locations,
and therapeutic uses in the treatment of a range of channelopathies.
Additionally, structures and functions of selected ion channels are
briefly described to aid in the rational design of channel modulators.
Overall, allosteric modulation represents an innovative targeting
approach, and the corresponding modulators provide an abundant but
challenging landscape for novel therapeutics targeting ligand-gated
and voltage-gated ion channels.