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Bis-Quinolinium Cyclophanes: Highly Potent and Selective Non-Peptidic Blockers of the Apamin-Sensitive Ca2+-Activated K+ Channel

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Abstract:

Small conductance Ca2+-activated K+ (SKCa) channels comprise an important subclass of K+ channels. Selective blockade of SKCa channels may find application in the therapy of myotonic muscular dystrophy, gastrointestinal dysmotilities, memory disorders, narcolepsy, and alcohol abuse. In the cyclophanes described herein the two 4-aminoquinolinium groups are joined at the ring N atoms (linker L) and at the exocyclic N atoms (linker A). When both the spacer A and L 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) shows activity in the low nanomolar range. Furthermore, the results with the present series add significantly to the structure-activity knowledge in the field, since they incorporate the first example of molecules in which the activity depends critically on the nature of the linkers joining the two quinolinium (Q) groups. Later on, a novel series of bisquinolinium bis-alkylene cyclophanes was described. The biological results of the present series add support to the suggestion that the linkers of the two Q groups do not form direct interactions with the channel protein but comprise a molecular support for the two Q groups. Two important structural features of the pharmacophore for SKCa channel blockade have been identified. These are (1) an optimum distance of ca. 5.8 Å between the centroids of the pyridinium rings of the two quinolinium groups, and (2) a preference for conformations having the Q groups in a synperiplanar orientation.

Keywords: Antiperiplanar conformations; SK3 channel; apamin; bis-quinolinium compounds; cyclophanes; dequalinium; small conductance Ca2+-activated K+; synperiplanar conformations

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986708784534983

Affiliations: Departamento de Quimica Farmaceutica y Organica, Facultad de Farmacia, c/ Campus de Cartuja s/n, 18071 Granada, Spain.

Publication date: June 1, 2008

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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