SKA-121

K_Ca3.1 is a calcium-activated K⁺ channel. K_Ca2/3 channels are voltage-independent and share a Ca²⁺/calmodulin-mediated gating mechanism¹.

K_Ca3.1 and K_Ca2 channels are expressed in cells and enable them to hyperpolarize in order to regulate Ca²⁺ influx through inward rectifier Ca²⁺ channels, pass on hyperpolarization through gap junctions, or regulate firing frequency by preventing an untimely or premature action potential initiation². Pharmacological activation of K_Ca channels has therefore been suggested as a treatment for various diseases. The different specific activities of K_Ca2 and K_Ca3.1 channels create a difference between the activators of these two types of channels. K_Ca2 activators can potentially reduce neuronal excitability in central nervous system disorders like epilepsy and ataxia. K_Ca3.1 activators could be useful as endothelial targeted antihypertensives and to enhance fluid secretion in the airways in cystic fibrosis^3,4.

The positive-gating modulators used until today have low selectivity and affect both K_Ca2 and K_Ca3.1, making it impossible to differentiate the phenotypes of these two receptors. To avoid K_Ca2 channel-mediated side effects, it is highly desirable to identify selective K_Ca3.1 activators that could be used as pharmacological tools to further dissect the in vivo role of K_Ca3.1 in blood pressure control and to help determine whether K_Ca3.1 activators could eventually be developed into a new class of endothelial-targeted antihypertensives. SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), a compound generated through an isosteric replacement approach, activates K_Ca3.1 with an EC₅₀ of 111 nM, exhibits 40- to 80-fold selectivity over the three K_Ca2 channels and lowers blood pressure in mice as determined by telemetry without exerting K_Ca2 channel-mediated effects on HR⁵.