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Compounds that block both intermediate‐conductance (IK Ca ) and small‐conductance (SK Ca ) calcium‐activated potassium channels
Author(s) -
MalikHall M,
Ganellin C R,
Galanakis D,
Jenkinson D H
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703233
Subject(s) - chemistry , conductance , apamin , potassium , calcium , ionophore , calcium activated potassium channel , potassium channel , stereochemistry , biophysics , mathematics , organic chemistry , combinatorics , biology
Nine bis‐quinolinyl and bis‐quinolinium compounds related to dequalinium, and previously shown to block apamin‐sensitive small conductance Ca 2+ ‐activated K + channels (SK Ca ), have been tested for their inhibitory effects on actions mediated by intermediate conductance Ca 2+ ‐activated K + channels (IK Ca ) in rabbit blood cells. In most experiments, a K + ‐sensitive electrode was employed to monitor the IK Ca ‐mediated net loss of cell K + that followed the addition of the Ca 2+ ionophore A23187 (2 μ M ) to red cells suspended at an haematocrit of 1% in a low K + (0.12–0.17 m M ) solution. The remainder used an optical method based on measuring the reduction in light transmission that occurred on applying A23187 (0.4 or 2 μ M ) to a very dilute suspension of red cells (haematocrit 0.02%). Of the compounds tested, the most potent IK Ca blocker was 1,12 bis[(2‐methylquinolin‐4‐yl)amino]dodecane (UCL 1407) which had an IC 50 of 0.85±0.06 μ M (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 IK Ca 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 IC 50 of 1.8±0.1 μ 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 (IC 50 2.7±0.3 μ M ). A bis‐aminoquinolium cyclophane (UCL 1684) had little IK Ca blocking action despite its great potency at SK Ca channels (IC 50 4.1±0.2 n M ). The main outcome is the identification of new intermediate‐conductance Ca 2+ ‐activated K + channel blockers with a wide range of IK Ca /SK Ca selectivities.British Journal of Pharmacology (2000) 129 , 1431–1438; doi: 10.1038/sj.bjp.0703233