Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-d]oxazol-2-amine (SKA-121).

ABSTRACT: Intermediate-conductance (K_Ca3.1) and small-conductance (K_Ca2) calcium-activated K⁺ channels are gated by calcium binding to calmodulin (CaM) molecules associated with the calmodulin-binding domain (CaM-BD) of these channels. The existing K_Ca activators, such as naphtho[1,2-d]thiazol-2-ylamine (SKA-31), 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309), and 1-ethylbenzimidazolin-2-one (EBIO), activate both channel types with similar potencies. In a previous chemistry effort, we optimized the benzothiazole pharmacophore of SKA-31 toward K_Ca3.1 selectivity and identified 5-methylnaphtho[2,1-d]oxazol-2-amine (SKA-121), which exhibits 40-fold selectivity for K_Ca3.1 over K_Ca2.3. To understand why in

SUBMITTER: Brown BM 

PROVIDER: S-EPMC5588545 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature