Evaluation of Novel Cloxyquin Analogs for K2P18.1 Channel Modulation.

K2P18.1 (TRESK) displays one of the most unusual two pore domain potassium channels, that is associated with different neurological and immune-related diseases emphasizing the therapeutic potential of K2P18.1 activators. Previous studies identified cloxyquin and nitroxoline as lead compounds that do not alter the function of other K2P channels. Although their 8-OH group is crucial for channel activation, 8-hydroxyquinolines are known for various effects including metal chelation and antibacterial properties increasing the risk of side effects. Therefore, we synthesized 14 quinoline derivatives to search for other tolerated substitutions in 8-position. Activity determination using two-electrode voltage clamp (TEVC) revealed that four derivatives achieved moderate inhibitory or stimulatory activity. Among these, benzaldimine 3d represents a new extended scaffold that unexpectedly increases K2P18.1 channel activity by about 60% at 100 µM. Docking studies suggest that despite the enlarged structure, 3d is still able to achieve in silico interactions with important amino acids from the cloxyquin binding site. However, its usability in vitro is limited by hydrolysis leading to a compound half-life of 39 min in aqueous solutions. Nevertheless, the identification of a possible scaffold extension for K2P18.1 channel activators opens a new opportunity for future compound diversification.