Cloxyquin has been reported as a specific activator of TRESK (K2P18.1, TWIK-related spinal cord K+ channel) background potassium channel. In this study, we have synthetized chemically modified analogues of cloxyquin and tested their effects on TRESK and other K2P channels. The currents of murine K2P channels, expressed heterologously in Xenopus oocytes, were measured by two-electrode voltage clamp, whereas the native background K+ conductance of mouse dorsal root ganglion (DRG) neurons was examined by the whole-cell patch clamp method. Some of the analogues retained the activator character of the parent compound, but more interestingly, other derivatives inhibited mouse TRESK current. The inhibitor analogues (A2764 and A2793) exerted state-dependent effect. The degree of inhibition by 100 µM A2764 (77.8±1.5%, n=6) was larger in the activated state of TRESK (i.e. after calcineurin-dependent stimulation) than in the resting state of the channel (42.8±4.3% inhibition, n=7). The selectivity of the inhibitor compounds was tested on several K2P channels. A2793 inhibited TASK-1 (100 µM, 53.4±6%, n=5), while A2764 was more selective for TRESK, it only moderately influenced TREK-1 and TALK-1. The effect of A2764 was also examined on the background K+ currents of DRG neurons. A subpopulation of DRG neurons, prepared from wild-type animals, expressed background K+ currents sensitive to A2764, while the inhibitor did not affect the currents in the DRG neurons of TRESK-deficient mice. Accordingly, A2764 may prove to be useful for the identification of TRESK current in native cells, and for the investigation of the role of the channel in nociception and migraine.