Bis-quinolinium cyclophanes: highly potent and selective non-peptidic blockers of the apamin-sensitive Ca2+-activated K+ channel.
Curr Med Chem
; 15(13): 1305-15, 2008.
Article
en En
| MEDLINE
| ID: mdl-18537610
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.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Apamina
/
Compuestos de Quinolinio
/
Canales de Potasio Calcio-Activados
/
Bloqueadores de los Canales de Potasio
/
Alcanos
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
Idioma:
En
Revista:
Curr Med Chem
Asunto de la revista:
QUIMICA
Año:
2008
Tipo del documento:
Article
País de afiliación:
España