Modulation of recombinant and native neuronal SK channels by the neuroprotective drug riluzole

Targeting potassium channels to treat cerebellar ataxia

“…This possibility is supported by recent clinical trials with the compound riluzole, whose targets include K Ca channels 21, 22. Although riluzole shares common ion channel targets with chlorzoxazone and baclofen, its effect on improving motor dysfunction is likely to be modest, as it has a relatively low potency for both K Ca channels and subthreshold‐activated potassium channels 23, 24. Compounds with increased target specificity and potency are likely to be more effective than riluzole.…”

“…Recently, clinical trials for the compound riluzole have demonstrated therapeutic promise for the treatment of several forms of SCA 21, 22. The known targets of riluzole include calcium‐activated potassium channels, some subthreshold‐activated potassium channels, and voltage‐gated sodium channels 23, 24. It is important to determine which ion channel targets are relevant for treating symptoms in order to identify effective drugs with reduced potential for off‐target effects.…”

Pharmacological gating modulation of small- and intermediate-conductance Ca2+-activated K+channels (KCa2.x and KCa3.1)

“…36 Another compound, riluzole, the only drug FDA approved for treatment of amyotropic lateral sclerosis (ALS), was shown to activate K Ca 3.1/K Ca 2.x channels even more potently than 1-EBIO. 37 Despite having a very "rich" ion channel pharmacology, including block of voltagedependent Na C (Na v ) channels (but not glutamate receptors even though its therapeutic action is often referred to as being anti-glutamatergic), the activation of KCNN channels is among riluzole's most potent effects. 38 Two molecules also belonging to the benzimidazole/benzothiazole prototype K Ca activator class are NS309, a very potent molecule (EC 50 10-20 nM for K Ca 3.1 and »600 nM for K Ca 2 channels) and very useful for in vitro mechanistic work, and SKA-31, which was optimized from riluzole with the aim of getting better selectivity (inactive on Na v channels) and maintaining good in vivo properties.…”

Activity-Dependent Regulation of the Dopamine Phenotype in the Adult Substantia Nigra: Prospects for Treating Parkinson's Disease

“…voltageactivated Na+, glutamate receptors and SK channels). It activates SK channels at concentrations ≥3μM (Cao et al 2002, Grunnet et al 2001) and at 30μM (direct injection) it increases the number of TH+ SNc cells in normal mice (Aumann et al 2011). We therefore tested its ability to increase the number of TH+ SNc in the PD model.…”