Compounds that block both intermediate-conductance (IKCa) and small-conductance (SKCa) calcium-activated potassium channels.
British Journal of Pharmacology
1431 - 1438.
1 Nine bis-quinolinyl and bis-quinolinium compounds related to dequalinium, and previously shown to black 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. 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+ ionophore 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 based on measuring the reduction in light. transmission that occurred on applying A23187 (0.4 or 2 mu M) to a very dilute suspension of red cells (haematocrit 0.02%). 3 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 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 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. 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-methylquinolinium-4- yl]amino]-10-[N'-(2-methylquinolinium-4yl)amino] decane (trifluoroacetate) which had an IC50 of 1.8+/-0.1 mu M 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 mu M). 6 A bis-aminoquinolium cyclophane (UCL 1684) had little IKCa blocking action despite its great potency at SKCa channels (IC50 4.1 +/- 0.2 nM). 7 The main outcome is the identification of new intermediate-conductance Ca2+-activated Kf channel blockers with a wide range of IKCa/SKCa selectivities
|Title:||Compounds that block both intermediate-conductance (IKCa) and small-conductance (SKCa) calcium-activated potassium channels|
|Additional information:||Journal Article APR 298KN Jenkinson DH Univ London Univ Coll, Dept Pharmacol, Gower St, London WC1E 6BT, England BRIT J PHARMACOL|
|Keywords:||AFTERHYPERPOLARIZATION, APAMIN, As, bisquinolinium compounds, Blood, Blood Cells, Ca2+-activated K+ channel, CA2+-ACTIVATED K+ CHANNELS, cell, CELLS, channels, clotrimazole, DEQUALINIUM, effects, ELECTRODE, HEPATOCYTES, HIGH-AFFINITY, HUMAN ERYTHROCYTES, IDENTIFICATION, IKCa blocker, intermediate conductance K+ channel, LIGHT, LIPOPHILICITY, MEMBERS, MM, MONITOR, neurons, outcome, Potassium, Potassium Channels, POTENT, QUININE, rabbit, rabbit blood cells, RANGE, RED-CELLS, REDUCTION, SELECTIVITY, Sensitivity, SERIES, SKCa blocker, SMALL-CONDUCTANCE, superior cervical ganglion, TIME, transmission, UCL, UCL 1407, UCL 1684|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of)
UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry
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