Synthesis, molecular modeling, and pharmacological testing of bis-quinolinium cyclophanes: Potent, non-peptidic blockers of the apamin-sensitive Ca2+-activated K+ channel

The synthesis and pharmacological testing of two series of novel bis-quinol inium cyclophanes as blockers of the apamin-sensitive Ca2+-activated K+ (SK Ca) 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 ato ms (linker A). In those cases where A and L contain two or more aromatic ri ngs 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 b locking potency changes dramatically with simple structural variations in t he 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 cha nnel blocker described to date. Conformational analysis on the smaller cycl ophanes using molecular modeling techniques suggests that the differences i n the blocking potencies of the compounds may be attributable to their diff erent conformational preferences.