NS-309

NS-309. A Positive Modulator of Small- and Intermediate-Conductance K_Ca Channels.

Ca²⁺-activated potassium channels (K_Ca) are a group of 6/7-TMпїЅproteins that selectively transport K⁺ ions across biologI_cal membranes. They are broadly classified into three subtypes: SK, IK and BK channels (small, intermediate and big conductance, respectively). Three SK channel subtypes exist (SK1-3, K_Ca2.1-3) and are widely distributed in the central nervous system (CNS) as well as in the periphery.
They constitute a molecular family of voltage-independent channels with the peripherally expressed intermediate conductance Ca²⁺-activated K⁺ channel (IK, K_Ca3.1), but differ in their distribution; SK channels are predominantly expressed in excitable cells, whereas IK channels mostly are found in non-excitable cells.
NS-309 is a selective and potent activator of K_Ca3.1 and K_Ca2 channels, whereas it is devoid of effect on BK (K_Ca1.1) type channels. Whole cell currents, obtained by voltage ramps applied to HEK293 cells, reveal that human K_Ca2 channels are two to four times less sensitive to NS-309 than human K_Ca3.1; NS-309 increases the K_Ca2 currents with an EC₅₀ value of 30 nM, whereas an EC₅₀ value of 10 nM is inferred for the K_Ca3.1 currents.
NS-309 possesses a therapeutic potency for cystic fibrosis and chronic obstructive pulmonary disease by improving epithelial Cl- secretion via K_Ca3.1 channel activation and for moderating neuronal hyperexcitability by enhancing apamin-sensitive after-hyperpolarizing current (IAHP, mediated by K_Ca2 channels).

NS-309 shows substantial block of L-type Ca²⁺ channel. It concentration-dependently inhibits the I_ca in smooth muscle cells isolated from mouse urinary bladder with an IC₅₀ value of 10.6 μM. However, the specificity of NS-309 for the K_Ca3.1 channel over VDCC is much higher.

Ion Channel Modulators; K⁺ Channel Openers

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