Synthetic resin acid derivatives selectively open the hK(V)7.2/7.3 channel and prevent epileptic seizures

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Dokumenter

  • Nina E. Ottosson
  • Malin Silvera Ejneby
  • Xiongyu Wu
  • Argel Estrada-Mondragon
  • Michelle Nilsson
  • Urban Karlsson
  • Melanie Schupp
  • Rognant, Salomé
  • Thomas Andrew Jepps
  • Peter Konradsson
  • Fredrik Elinder

Objective 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.

Methods 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.

Results 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.

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

OriginalsprogEngelsk
TidsskriftEpilepsia
Vol/bind62
Udgave nummer7
Sider (fra-til)1744-1758
ISSN0013-9580
DOI
StatusUdgivet - 2021

ID: 272246116