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

1 Nine bis-quinolinyl and bis-quinolinium compounds related to dequalinium, and previously shown to black apamin-sensitive small conductance Ca2+-acti vated K+ channels (SKCa), have been tested for their inhibitory effects on actions mediated by intermediate conductance Ca2+-activated K+ channels (IK Ca) in rabbit blood cells. 2 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+ i onophore A23187 (2 mu M) 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 base d on measuring the reduction in light. transmission that occurred on applyi ng A23187 (0.4 or 2 mu M) to a very dilute suspension of red cells (haemato crit 0.02%). 3 Of the compounds tested, the most potent IKCa blocker was 1,12 bis[(2-met hylquinolin-4-yl)amino]dodecane (UCL 1407) which had an IC50 of 0.85+/-0.06 mu M (mean+/-s.d.mean). 4 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 suggest ed 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 clotrim azole. 5 Some quaternized members of the series were also active. The most potent was the monoquaternary UCL 1440 ((1-[N-[1-(3,5-dimelhoxybenzyl)-2-methylqui nolinium-4-yl]amino]-10-[N'-(2-methylquinolinium-4yl)amino] decane (trifluo roacetate) which had an IC50 of 1.8+/-0.1 mu M The corresponding bisquatern ary 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 mu M). 6 A bis-aminoquinolium cyclophane (UCL 1684) had little IKCa blocking actio n despite its great potency at SKCa channels (IC50 4.1 +/- 0.2 nM). 7 The main outcome is the identification of new intermediate-conductance Ca 2+-activated Kf channel blockers with a wide range of IKCa/SKCa selectiviti es.