Referenced in: none

Automatically associated channels: SK2 , SK3

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

Authors: Eduard Badarau, Sébastien Dilly, Fabien Dufour, Sylvie Poncin, Vincent Seutin, Jean-François Liégeois

Journal, date & volume: Bioorg. Med. Chem. Lett., 2011 Nov 15 , 21, 6756-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21978678

Abstract
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.