Evaluation of gambierol and its analogs for their inhibition of human K_v1.2 and cytotoxicity

Gambierol and its heptacyclic and tetracyclic analogs were tested for inhibitory activity against the human voltage-gated potassium channel K_v1.2 (hK_v1.2), which was stably expressed in Chinese hamster ovary (CHO) cells. Gambierol, the heptacyclic analog, and the tetracyclic analog inhibited the potassium current evoked by a step pulse from -80 mV to 40 mV. The IC₅₀ values for the three compounds were 0.75 ± 0.15 nM, 7.6 ± 1.2 nM, and 28 ± 4.0 nM (the mean ± SEM, n = 3), respectively. The cytotoxic activity was examined in order to assess a relationship between cytotoxicity and inhibition of the hK_v1.2. The IC₅₀ values for gambierol, the heptacyclic analog, and the tetracyclic analog in the wild-type CHO cells were 95 ± 7.1 μM, 6.5 ± 0.8 μM (the mean ± SEM, n = 3), and >100 μM (n = 3), respectively, whereas those in the CHO cells stably expressing hK_v1.2 were 78 ± 5.8 μM, 6.0 ± 1.0 μM (the mean ± SEM, n = 3), and >100 μM (n = 3). These results suggested that cytotoxicity is not triggered by inhibition of the human K_v1.2. The electrophysiological recording at the resting potential in the presence of gambierol, the heptacyclic analog, and the tetracyclic analog revealed the dose-dependent leak current, which was largest when the heptacyclic analog was administered to the cells. We thus propose that the leak current induced by these compounds might cause a fatal effect on the cultured cells.