Compounds that block both intermediate-conductance (IKCa) and small-conductance (SKCa) calcium-activated potassium channels

摘要

class="enumerated" style="list-style-type:decimal">Nine bis-quinolinyl and bis-quinolinium compounds related to dequalinium, and previously shown to block apamin-sensitive small conductance Ca²⁺-activated K⁺ channels (SKCa), have been tested for their inhibitory effects on actions mediated by intermediate conductance Ca²⁺-activated K⁺ channels (IKCa) in rabbit blood cells.In most experiments, a K⁺-sensitive electrode was employed to monitor the IKCa-mediated net loss of cell K⁺ that followed the addition of the Ca²⁺ ionophore (2 μM) to red cells suspended at an haematocrit of 1% in a low K⁺ (0.12–0.17 mM) solution. The remainder used an optical method based on measuring the reduction in light transmission that occurred on applying (0.4 or 2 μM) to a very dilute suspension of red cells (haematocrit 0.02%).Of the compounds tested, the most potent IKCa blocker was 1,12 bis[(2-methylquinolin-4-yl)amino]dodecane (UCL 1407) which had an IC50 of 0.85±0.06 μM (mean±s.d.mean).The inhibitory action of UCL 1407 and its three most active congeners was characterized by (i) a Hill slope greater than unity, (ii) sensitivity to an increase in external [K⁺], and (iii) a time course of onset that suggested use-dependence. Also, the potency of the nonquaternary compounds tested increased with their predicted lipophilicity. These findings suggested that the IKCa blocking action resembles that of cetiedil rather than of clotrimazole.Some quaternized members of the series were also active. The most potent was the monoquaternary UCL 1440 ((1-[N-[1-(3,5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino]-10-[N′-(2-methylquinolinium-4yl)amino] decane (trifluoroacetate) which had an IC50 of 1.8±0.1 μM. The corresponding bisquaternary UCL 1438 (1,10-bis[N-[1-(3,5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino] decane bis(trifluoroacetate) was almost as active (IC50 2.7±0.3 μM).A bis-aminoquinolium cyclophane (UCL 1684) had little IKCa blocking action despite its great potency at SKCa channels (IC50 4.1±0.2 nM).The main outcome is the identification of new intermediate-conductance Ca²⁺-activated K⁺ channel blockers with a wide range of IKCa/SKCa selectivities.