Nonsteroidal Anti-Inflammatory Drugs as Modulators of Cation Channels: Fenamates Repurposing in Channelopathies

Cationic ion channels are transmembrane proteins that regulate the flux of cations (potassium, sodium, and calcium) across cell membrane, playing a pivotal role in many cellular functions. Disruptions of their activity can lead to the so-called genetic or acquired channelopathies, a heterogeneous group of diseases that affect multiple human systems. Fenamates, a class of nonsteroidal anti-inflammatory drugs, has recently emerged as modulators of cationic ion channels highlighting the possibility of their repurposing for the treatment ion channel-related disorders, such as channelopathies, chronic pain, epilepsy, cardiac arrhythmias, and cancers. In this review, the ability of fenamates (i.e. niflumic, flufenamic, mefenamic, meclofenamic, and tolfenamic acids) to differentially modulate the activity of cationic ion channels is described. Overall, preclinical and clinical studies suggest that fenamates represent a promising class of compounds for drug repurposing and for the development of new molecules, offering novel therapeutic opportunities for patients affected by ion channel-related disorders.