Bis-quinolinium cyclophanes: highly potent and selective non-peptidic blockers of the apamin-sensitive Ca2+-activated K+ channel.

Abstract:

:Small conductance Ca(2+)-activated K(+) (SK(Ca)) channels comprise an important subclass of K(+) channels. Selective blockade of SK(Ca) 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 bis-quinolinium 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 SK(Ca) channel blockade have been identified. These are (1) an optimum distance of ca. 5.8 A 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.

journal_name

Curr Med Chem

authors

Conejo-García A,Campos JM

doi

10.2174/092986708784534983

subject

Has Abstract

pub_date

2008-01-01 00:00:00

pages

1305-15

issue

13

eissn

0929-8673

issn

1875-533X

journal_volume

15

pub_type

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