Resin-Acid Derivatives Open the hKV7.2/7.3 Channel and have Antiepileptic Effects in a Zebrafish Larvae Model

The voltage-gated potassium channel hKv7.2/7.3 set the resting membrane potential and thereby regulate excitability of neurons. It is a target for the antiepileptic, channel-opening, drug retigabine. The problem with retigabine is that it causes adverse effects, partly because of its low hKv7.2/7.3 versus hKv7.4 channel selectivity and has therefore been withdrawn from the market. However, retigabine validated opening of the hKv7.2/7.3 channel as an antiepileptic strategy. Our aim is to develop selective hKv7.2/7.3 channel openers with antiepileptic effects. We have developed derivatives of naturally occurring resin acids, some of them as potent as retigabine. The derivatives open the hKv7.2/7.3 channel by an electrostatic mechanism, acting on the voltage sensor. This site of action is different from the retigabine-binding site and makes it possible to gain selectivity between hKv7.2/7.3 and hKv7.4. Small structural alterations of our derivatives had different effects on hKv7.2/7.3 and hKv7.4. To investigate potential off-target effects we tested our compounds on the cardiac hERG and hNav1.5 channels. At 10 μM, none of the compounds blocked the current nor shifted the voltage dependencies of the hERG or the hNav1.5 channel. To investigate the antiepileptic effect, we induced epileptic seizures in zebrafish larvae by a chemoconvulsant (PTZ) and recorded the electrical brain activity with extracellular electrodes. The epileptic seizures were prevented by retigabine (at 10 μM), and our potential lead compounds had similar effects at the same concentration. By opening the hKv7.2/7.3 channel and preventing epileptic seizures in an in vivo model, our resin-acid derivatives thus show the potential to be developed into a new type of antiepileptic drug.