Investigation of the structure activity relationship of flufenamic acid derivatives at the human TRESK channel K 2P 18.1

Selective and state‐dependent activation of TRESK (K2P18.1) background potassium channel by cloxyquin

“…The pharmaceutical industry has taken an interest in TRESK as a drug target (Bruner et al , ). In a recent report (Monteillier et al , ), the prostaglandin synthesis inhibitor flufenamic acid was reported to activate TRESK, but this drug also acts on several other K 2P channels. Still, its derivatives were further examined; some of them proved to be slightly more potent, while others were inhibitors of TRESK.…”

“…Only a few relatively specific modulators of K 2P channel activity have been described so far. Sanshool (Bautista et al , ), isobutylalkenyl amide (Tulleuda et al , ), lamotrigine (Kang et al , ; Liu et al , ), aristolochic acid (Veale and Mathie, ), zinc and mercuric ions (Czirják and Enyedi, ), capsaicin (Beltran et al , ), loratadine (Bruner et al , ), flufenamic acid (Monteillier et al , ) and other antidepressant or nonsteroidal anti‐inflammatory drugs (Park et al , ) have been well documented to modulate TRESK activity; however, they are also known to influence other pharmacological targets in addition to this K 2P channel. A possible explanation for the lack of specific and high‐affinity pharmacological tools could be the extracellular cap domain found in the structure of K 2P channels which prevents free access to the extracellular side of the pore domain (Brohawn et al , ; Miller and Long, ).…”

TRESK (K2P18.1) Background Potassium Channel Is Activated by Novel-Type Protein Kinase C via Dephosphorylation

“…Recently, it has been suggested that the frameshift-induced alternative translation initiation and the dominant negative effect of the truncated TRESK subunit on TREK-1 and TREK-2 channels are responsible for migraine pathogenesis (Royal et al, 2019). Although a highly selective TRESK inhibitor is not yet available, great efforts have been made to identify pharmacological compounds modulating this putative drug target (Czirják and Enyedi, 2006b;Bautista et al, 2008;Kang et al, 2008;Beltrán et al, 2013;Kim et al, 2013;Wright et al, 2013;Monteillier et al, 2016;Park et al, 2016;Veale and Mathie, 2016;Castellanos et al, 2018;Park et al, 2018).…”

The Background K+ Channel TRESK in Sensory Physiology and Pain

“…Besides the activating effects of volatile anesthetics on TRESK and other K 2P channels, only a few compounds have been described as TRESK activators. Flufenamic acid, BL-1249, and its synthetic derivatives are TRESK openers that seem to act through a stabilization of an open state of the channel [73]. Using a baculovirus TRESK FluxOR cell-based assay, Wright et al identified cloxyquin (5-chloroquinolin-8-ol), an old drug used to treat intestinal infections due to its anti-amoebic, anti-bacterial and anti-fungal properties [74].…”