RT Journal Article
SR Electronic
T1 New Positive KCa Channel Gating Modulators with Selectivity for KCa3.1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.093286
DO 10.1124/mol.114.093286
A1 Nichole Coleman
A1 Brandon M. Brown
A1 Aida Olivan-Viguera
A1 Vikrant Singh
A1 Marilyn M. Olmstead
A1 Marta Sofia Valero
A1 Ralf Kohler
A1 Heike Wulff
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/06/23/mol.114.093286.abstract
AB Small-conductance (KCa2) and intermediate-conductance (KCa3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309 or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate KCa2.2 and KCa2.3 channels. We here performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 towards KCa3.1 selectivity. We have identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200-400 fold selective over representative KV (KV1.3, KV2.1, KV3.1 and KV11.1), NaV (NaV1.2, NaV1.4, NaV1.5 and NaV1.7) as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator, which shift the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not KCa3.1-/- mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-live and to be much more brain penetrant than SKA-121 not only lowered blood pressure but also drastically reduced heart rate presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121 we have generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutically potential of KCa3.1 activation.