Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a New Activator of KCa2 and KCa3.1 Potassium Channels, Potentiates the Endothelium-Derived Hyperpolarizing Factor Response and Lowers Blood Pressure

Abstract

Small-conductance (KCa2.1-2.3) and intermediate-conductance (KCa3.1) calcium-activated K ϩ channels are critically involved in modulating calcium-signaling cascades and membrane potential in both excitable and nonexcitable cells. Activators of these channels constitute useful pharmacological tools and potential new drugs for the treatment of ataxia, epilepsy, and hypertension. Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies.

Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole

“…These experiments focused on the effects of riluzole on the medium afterhyperpolarization, as its inhibition strongly increases HM repetitive firing frequency . Despite reports that riluzole potently enhances SK Ca 2ϩ -dependent K ϩ current in cell expression systems (Cao et al 2002;Sankaranarayanan et al 2009), evidence that the action potential afterhyperpolarization in neurons is increased by riluzole is scant (BeltranParrazal and Charles 2003;Cao et al 2002) and the lack of any effect of riluzole on the medium afterhyperpolarization seen here is in accord with other reports (Del Negro et al 2008;Kuo et al 2006;Miles et al 2005;van Zundert et al 2008). However, it should be noted that riluzole clearly inhibited a voltage-sensitive Ca 2ϩ current in HMs, and this effect might be expected to reduce Ca 2ϩ influx during the action potential and, in turn, reduce Ca 2ϩ -dependent K ϩ currents.…”

Targeting potassium channels to treat cerebellar ataxia

“…SKA‐31 is a highly selective activator of SK2 and IK channels 45. The targets of chlorzoxazone are, however, largely unknown.…”

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

“…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. 38,39 The very close analogs, SKA-111 and SKA-121, exhibit much higher K Ca 3.1/K Ca 2 selectivity, and accentuate the primary role of the benzimidazole/benzothiazole series as being K Ca 3.1 activators.…”

“…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. 38,39 The very close analogs, SKA-111 and SKA-121, exhibit much higher K Ca 3.1/K Ca 2 selectivity, and accentuate the primary role of the benzimidazole/benzothiazole series as being K Ca 3.1 activators. 40 In contrast to the above mentioned molecules, which show little selectivity between the K Ca 2 family members, CyPPA and its more potent congener NS13001 have fundamentally different structures and also changed selectivity profiles (Fig.…”

“…62,63 Mice deficient in K Ca 3.1 and/or K Ca 2.3 exhibit impaired EDH responses and show a~10 mmHg increase in mean arterial blood pressure, 28,29 while SKA-31 lowers blood pressure in normotensive and hypertensive mice as well as in conscious, normotensive dogs. 29,38,64 Since the blood pressure lowering effect of SKA-31 is absent in KCa3.1 ¡/¡ mice and higher doses of SKA-31 induce sedation and lower heart rate through central K Ca 2 channel activation, 65 it seems desirable to identify K Ca 3.1 selective positive gating modulators in order to help investigate whether such compounds could be developed into a new class of endothelial targeted antihypertensives. 63 This objective recently seems to have been achieved with the demonstration that the K Ca 3.1 selective SKA-121 lowers blood pressure in normotensive and hypertensive mice without affecting heart rate.…”