The Small Molecule NS11021 Is a Potent and Specific Activator of Ca2+-Activated Big-Conductance K+ Channels

Abstract

Large-conductance Ca 2ϩ -and voltage-activated K ϩ channels (Kca1

Structure–Activity Relationships of a Novel Group of Large‐Conductance Ca2+‐Activated K+ (BK) Channel Modulators: The GoSlo‐SR Family

“…To illustrate how efficacious the GoSlo-SR family of compounds were, we compared the effects of two well established BK channel openers, NS1619 [21] and NS11021 [12] on these currents. Figure 5A shows a typical example in which we applied NS1619 (orange line) at a concentration of 10 µM, to a patch containing approximately 23 BK channels.…”

“…[6] Consequently, the pharmaceutical industry has invested significantly in trying to target smooth muscle function by developing novel BK channel modulators to help treat disorders such as urinary incontinence. [6][7][8][9][10] Although a large number of chemically diverse BK channel openers have already been developed, [8,9] only a few studies [11][12][13] have focused on examining the effects of these compounds across a wide voltage range to include physiological potentials (~−100 mV to 0 mV). [10][11][12] Instead, the majority of studies have focused on the ability of compounds to open channels only at potentials some 50 to 100 mV more positive than a cell is ever likely to encounter in vivo.…”

“…[6][7][8][9][10] Although a large number of chemically diverse BK channel openers have already been developed, [8,9] only a few studies [11][12][13] have focused on examining the effects of these compounds across a wide voltage range to include physiological potentials (~−100 mV to 0 mV). [10][11][12] Instead, the majority of studies have focused on the ability of compounds to open channels only at potentials some 50 to 100 mV more positive than a cell is ever likely to encounter in vivo. It appears that the majority of BK channel openers developed to date would have little effect at physiological membrane potentials and this may explain their poor efficacy in clinical trials [7] and subsequent failure to progress to market.…”

“…This was not significantly different to the results obtained with 5k and suggests that although 5r was more efficacious than 5k, there was little difference in the potency of these two compounds on BK channels. Interestingly, the slope of the concentration effect curve for 5r (mean Hill slope 1.8; 95% Confidence Intervals 1.2 to 2.5) was steeper than for 5k (mean Hill slope 0.9; 95% Confidence Intervals 0.4 to 1.3), perhaps suggesting that there was a change in the extent of cooperativity of the binding sites when 5r was applied.To illustrate how efficacious the GoSlo-SR family of compounds were, we compared the effects of two well established BK channel openers, NS1619 [21] and NS11021 [12] on these currents. Figure 5A shows a typical example in which we applied NS1619 (orange line) at a concentration of 10 µM, to a patch containing approximately 23 BK channels.…”

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: Involvement of the S4/S5 linker and the S6 segment

“…These results suggest that BK channel activators could represent a novel therapeutic approach for treating overactive bladder. However, despite the development of a large number of BK channel openers over the last two decades (23)(24)(25)(26)(27)(28)(29), they have failed to progress through clinical trials, because they showed poor efficacy, presumably due to their lack of effect at physiological membrane potentials, combined with a reduction in BK channels in patients with overactive bladder (30).…”