New Positive Ca 2 1 - Activated K 1 Channel Gating Modulators with Selectivity for KCa 3 . 1 s
نویسندگان
چکیده
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 performed a structureactivity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC5
منابع مشابه
Negative Gating Modulation by (R)-N-(Benzimidazol-2-yl)- 1,2,3,4-tetrahydro-1-naphthylamine (NS8593) Depends on Residues in the Inner Pore Vestibule: Pharmacological Evidence of Deep-Pore Gating of KCa2 Channels □S
Acting as a negative gating modulator, (R)-N-(benzimidazol-2yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593) shifts the apparent Ca -dependence of the small-conductance Ca -activated K channels KCa2.1–2.3 to higher Ca 2 concentrations. Similar to the positive KCa channel-gating modulators 1-ethyl2-benzimidazolinone (1-EBIO) and cyclohexyl-[2-(3,5-dimethylpyrazol-1-yl)-6-methylpyrimidin-4-yl]-ami...
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