Synthesis and radioligand binding studies of bis-(8-isopropylisoquinolinium) derivatives as ligands for apamin-sensitive sites on cloned SK2 and SK3 channels
small conductance calcium-activated potassium channel; SK; pharmacophore; charged nitrogens; isoquinoline
Abstract :
[en] A structure-activity relationship study of N-methyl-laudanosine, a SK channel blocker, has indicated that the 6,7-dimethoxy group could be successfully replaced by a hydrophobic moiety such as an isopropyl substituent in position 8 of the isoquinoline ring. In the present study, bis-(8-isopropyl-isoquinolinium) derivatives (2a-e) were synthesized and tested for their affinity for cloned SK2 and SK3 channels in comparison with their 6,7-dimethoxy analogues (4a-f). Several ligands were investigated, both in flexible (propyl, butyl and pentyl) and rigid (m- or p-xylyl) series, the m-xylyl derivative (2d) having the best profile in terms of affinity and selectivity for
SK3/SK2 channels. Molecular studies showed that the optimal conformation of compound 2d fits well with our SK pharmacophore model.
Badarau, Eduard; Université de Liège - ULiège > Département de Pharmacie-CIRM / Giga-Neurosciences > Chimie pharmaceutique / Pharmacologie
Dilly, Sébastien ; Université de Liège - ULiège > Département de Pharmacie-CIRM / Giga-Neurosciences > Chimie pharmaceutique / Pharmacologie
Dufour, Fabien; Université de Liège - ULiège > Département de Pharmacie-CIRM / Giga-Neurosciences > Chimie pharmaceutique / Pharmacologie
Poncin, Sylvie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Seutin, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Liégeois, Jean-François ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Language :
English
Title :
Synthesis and radioligand binding studies of bis-(8-isopropylisoquinolinium) derivatives as ligands for apamin-sensitive sites on cloned SK2 and SK3 channels
Publication date :
15 November 2011
Journal title :
Bioorganic and Medicinal Chemistry Letters
ISSN :
0960-894X
eISSN :
1464-3405
Publisher :
Elsevier Science, Oxford, United Kingdom
Volume :
21
Issue :
22
Pages :
6756-6759
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
SK channels
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] ULiège FSR - Université de Liège. Fonds spéciaux pour la recherche [BE] SPW DGO6 - Service Public de Wallonie. Economie, Emploi, Recherche [BE]
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