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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.