Synthetic resin acid derivatives selectively open the hK(V)7.2/7.3 channel and prevent epileptic seizures
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Synthetic resin acid derivatives selectively open the hK(V)7.2/7.3 channel and prevent epileptic seizures. / Ottosson, Nina E.; Ejneby, Malin Silvera; Wu, Xiongyu; Estrada-Mondragon, Argel; Nilsson, Michelle; Karlsson, Urban; Schupp, Melanie; Rognant, Salome; Jepps, Thomas Andrew; Konradsson, Peter; Elinder, Fredrik.
I: Epilepsia, Bind 62, Nr. 7, 2021, s. 1744-1758 .Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Synthetic resin acid derivatives selectively open the hK(V)7.2/7.3 channel and prevent epileptic seizures
AU - Ottosson, Nina E.
AU - Ejneby, Malin Silvera
AU - Wu, Xiongyu
AU - Estrada-Mondragon, Argel
AU - Nilsson, Michelle
AU - Karlsson, Urban
AU - Schupp, Melanie
AU - Rognant, Salome
AU - Jepps, Thomas Andrew
AU - Konradsson, Peter
AU - Elinder, Fredrik
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - epilepsy
KW - excitability
KW - potassium channel opener
KW - POTASSIUM CHANNELS
KW - KV7 CHANNELS
KW - EXPRESSION
KW - MODULATION
KW - GENE
U2 - 10.1111/epi.16932
DO - 10.1111/epi.16932
M3 - Journal article
C2 - 34085706
VL - 62
SP - 1744
EP - 1758
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 7
ER -
ID: 272246116