Positive KCa channel gating modulators with selectivity for KCa3.1 (1057.6)

Abstract

Intermediate and small‐conductance Ca2+ activated K+ (KCa) channels regulate membrane excitability and Ca2+ signaling. Pharmacological activation of these voltage‐independent channels has therefore been suggested for the treatment of various diseases. While KCa2 activators can potentially reduce neuronal excitability in CNS disorders, selective KCa3.1 activators could be useful as endothelial targeted antihypertensives. KCa channels are gated by Ca2+ binding to a constitutively associated calmodulin at the C‐terminus. Recent work by Zhang et al. (Zheng M. 2012 Nat Commun 3:1021) demonstrated that the benzimidazolone 1‐EBIO binds at the interface of the CAM N‐lobe and the calmodulin binding domain (CAMBD) of KCa2.2. Mutations of A477V/L480M and A477I in KCa2.2 were shown to increase and decrease potency of 1‐EBIO, respectively. Here we report that the same mutations (A625V/L628M and A625I) in KCa2.3 also alter the potency of KCa2/3 activators of the benzothiazole class such as SKA‐31. However, like 1‐EBIO and NS309, SKA‐31 suffers from a lack of selectivity between KCa3.1 and KCa2 channels. Via a structure activity relationship study we have optimized the pharmacophore of SKA‐31 and have now identified several compounds that display 40 to 160‐fold selectivity for KCa3.1 over KCa2.3. SKA‐121, a compound generated through an isosteric replacement approach, lowers blood pressure in mice as determined by telemetry without exerting KCa2 channel mediated effects on heart rate.Grant Funding Source: Supported by a NIGMS funded T32GM099608