Synthesis and radioligand binding studies of bis-(8-isopropyl-isoquinolinium) derivatives as ligands for apamin-sensitive sites on cloned SK2 and SK3 channels

被引：6
作者：
Badarau, Eduard [1 ,2 ,3 ,4 ]
Dilly, Sebastien [1 ,2 ,3 ,4 ]
Dufour, Fabien [1 ,2 ,3 ,4 ]
Poncin, Sylvie [3 ,4 ]
Seutin, Vincent [3 ,4 ]
Liegeois, Jean-Francois [1 ,2 ]
机构：
[1] Univ Liege, Med Chem Lab, B-4000 Liege 1, Belgium
[2] Univ Liege, CIRM, B-4000 Liege 1, Belgium
[3] Univ Liege, Pharmacol Lab, B-4000 Liege 1, Belgium
[4] Univ Liege, GIGA Neurosci, B-4000 Liege 1, Belgium
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 22期
关键词：
Small conductance calcium-activated potassium channel; SK; Pharmacophore; Charged nitrogens; Isoquinoline; BIS-TETRAHYDROISOQUINOLINE DERIVATIVES; CA2+-ACTIVATED K+ CHANNELS; SMALL-CONDUCTANCE; METHYL-LAUDANOSINE; BLOCKERS;
D O I：
10.1016/j.bmcl.2011.09.043
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
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. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码：6756 / 6759
页数：4
相关论文
共 19 条
[11]   Molecular and cellular basis of small- and intermediate-conductance, calcium-activated potassium channel function in the brain [J].
Pedarzani, P. ;
Stocker, M. .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2008, 65 (20) :3196-3217
[12]   Synthesis, molecular modeling, and pharmacological testing of bis-quinolinium cyclophanes:: Potent, non-peptidic blockers of the apamin-sensitive Ca2+-activated K+ channel [J].
Rosa, JC ;
Galanakis, D ;
Piergentili, A ;
Bhandari, K ;
Ganellin, CR ;
Dunn, PM ;
Jenkinson, DH .
JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (03) :420-431
[13]   VERSATILE SYNTHESIS OF REISSERT COMPOUNDS [J].
RUCHIRAWAT, S ;
PHADUNGKUL, N ;
CHUANKAMNERDKARN, M ;
THEBTARANONTH, C .
HETEROCYCLES, 1977, 6 (01) :43-46
[14]  
Sailer CA, 2002, J NEUROSCI, V22, P9698
[15]   Electrophysiological characterization of the SK channel blockers methyl-laudanosine and methyl-noscapine in cell lines and rat brain slices [J].
Scuvée-Moreau, J ;
Boland, A ;
Graulich, A ;
Van Overmeire, L ;
D'hoedt, D ;
Graulich-Lorge, F ;
Thomas, E ;
Abras, A ;
Stocker, M ;
Liégeois, JF ;
Seutin, V .
BRITISH JOURNAL OF PHARMACOLOGY, 2004, 143 (06) :753-764
[16]   Methyl-laudanosine:: A new pharmacological tool to investigate the function of small-conductance Ca2+-activated K+ channels [J].
Scuvee-Moreau, J ;
Liegeois, JF ;
Massotte, L ;
Seutin, V .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 302 (03) :1176-1183
[17]   Differential distribution of three Ca2+-activated K+ channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system [J].
Stocker, M ;
Pedarzani, P .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2000, 15 (05) :476-493
[18]   Small conductance calcium-activated potassium channels: From structure to function [J].
Weatherall, Kate L. ;
Goodchild, Samuel J. ;
Jane, David E. ;
Marrion, Neil V. .
PROGRESS IN NEUROBIOLOGY, 2010, 91 (03) :242-255
[19]   Bis-tetrahydroisoquinoline derivatives: Structure analysis of the three stereoisomers of 1,1′-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) [J].
Wouters, Johan ;
Elasaad, Kossay ;
Norberg, Bernadette ;
Graulich, Amaury ;
Liegeois, Jean-Francois .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2010, 45 (07) :3240-3244
12