Rosa, JC; Galanakis, D; Piergentili, A; Bhandari, K; Ganellin, CR; Dunn, PM; Jenkinson, DH; (2000) Synthesis, molecular modeling, and pharmacological testing of bis-quinolinium cyclophanes: Potent, non-peptidic blockers of the apamin-sensitive Ca2+-activated K+ channel. Journal of Medicinal Chemistry , 43 (3) 420 - 431.
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The synthesis and pharmacological testing of two series of novel bis-quinolinium cyclophanes as blockers of the apamin- sensitive Ca2+-activated K+ (SKCa) channel are presented. In these cyclophanes the two 4-aminoquinolinium groups are joined at the ring N atoms (linker L) and at the exocyclic N atoms (linker A). In those cases where A and L contain two or more aromatic rings each, the activity of the compound is not critically dependent upon the nature of the linkers. When A and L each have only one benzene ring, the blocking potency changes dramatically with simple structural variations in the linkers. One of these smaller cyclophanes having A = benzene-1,4- diylbis(methylene) and L = benzene-1,3-diylbis(methylene) (3j, 6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1,4)- dibenzenacyclodecaphanedium tritrifluoroacetate, UCL 1684) has an IC50 of 3 nM and is the most potent non-peptidic SKCa channel blocker described to date. Conformational analysis on the smaller cyclophanes using molecular modeling techniques suggests that the differences in the blocking potencies of the compounds may be attributable to their different conformational preferences
|Title:||Synthesis, molecular modeling, and pharmacological testing of bis-quinolinium cyclophanes: Potent, non-peptidic blockers of the apamin-sensitive Ca2+-activated K+ channel|
|Additional information:||Journal Article FEB 10 282YK Ganellin CR Univ London Univ Coll, Christopher Ingold Labs, Dept Chem, 20 Gordon St, London WC1H 0AJ, England J MED CHEM|
|Keywords:||analysis, APAMIN, As, ATOMS, BENZENE, Brain, Ca2+-activated K+ channel, CELLS, conformational analysis, DEQUALINIUM ANALOGS, difference, ENDOGENOUS EQUIVALENT, groups, LIGAND, May, MED, Molecular, nature, novel, Pharmacological, POLYPEPTIDES, POTASSIUM PERMEABILITY, POTENT, PREFERENCES, rings, SCORPION TOXIN, sensitive, SERIES, SKELETAL-MUSCLE, SMALL-CONDUCTANCE, synthesis, technique, UCL, 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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