Synthetic resin acid derivatives selectively open the hK_V 7.2/7.3 channel and prevent epileptic seizures

About one third of all patients with epilepsy have pharmacoresistant seizures. Thus there is a need for better pharmacological treatments. The human voltage-gated potassium (hK_V ) channel hK_V 7.2/7.3 is a validated antiseizure target for compounds that activate this channel. In a previous study we have shown that resin acid derivatives can activate the hK_V 7.2/7.3 channel. In this study we investigated if these channel activators have the potential to be developed into a new type of antiseizure drug. Thus we examined their structure-activity relationships and the site of action on the hK_V 7.2/7.3 channel, if they have unwanted cardiac and cardiovascular effects, and their potential antiseizure effect.

Ion channels were expressed in Xenopus oocytes or mammalian cell lines and explored with two-electrode voltage-clamp or automated patch-clamp techniques. Unwanted vascular side effects were investigated with isometric tension recordings. Antiseizure activity was studied in an electrophysiological zebrafish-larvae model.

Fourteen resin acid derivatives were tested on hK_V 7.2/7.3. The most efficient channel activators were halogenated and had a permanently negatively charged sulfonyl group. The compounds did not bind to the sites of other hK_V 7.2/7.3 channel activators, retigabine, or ICA-069673. Instead, they interacted with the most extracellular gating charge of the S4 voltage-sensing helix, and the effects are consistent with an electrostatic mechanism. The compounds altered the voltage dependence of hK_V 7.4, but in contrast to retigabine, there were no effects on the maximum conductance. Consistent with these data, the compounds had less smooth muscle-relaxing effect than retigabine. The compounds had almost no effect on the voltage dependence of hK_V 11.1, hNa_V 1.5, or hCa_V 1.2, or on the amplitude of hK_V 11.1. Finally, several resin acid derivatives had clear antiseizure effects in a zebrafish-larvae model.

The described resin acid derivatives hold promise for new antiseizure medications, with reduced risk for adverse effects compared with retigabine.