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

页码：6756 / 6759

页数：4

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