Synthesis, molecular modeling, and pharmacological testing of bis-quinolinium cyclophanes: potent, non-peptidic blockers of the apamin-sensitive Ca(2+)-activated K(+) channel

• Published in: Journal of medicinal chemistry 2000-02, Vol.43 (3), p.420-431
• Main Authors: Campos Rosa, J, Galanakis, D, Piergentili, A, Bhandari, K, Ganellin, C R, Dunn, P M, Jenkinson, D H
• Format: Article
• Language: English
• Subjects: Alkanes - chemical synthesis; Alkanes - chemistry; Alkanes - pharmacology; Animals; Apamin - pharmacology; Cells, Cultured; Models, Molecular; Molecular Conformation; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Calcium-Activated; Quinolinium Compounds - chemical synthesis; Quinolinium Compounds - chemistry; Quinolinium Compounds - pharmacology; Rats; Small-Conductance Calcium-Activated Potassium Channels; Structure-Activity Relationship; Superior Cervical Ganglion - cytology; Superior Cervical Ganglion - physiology
• ISSN: 0022-2623
• DOI: 10.1021/jm9902537

The synthesis and pharmacological testing of two series of novel bis-quinolinium cyclophanes as blockers of the apamin-sensitive Ca(2+)-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 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 IC(50) of 3 nM and is the most potent non-peptidic SK(Ca) 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.