title: Synthesis and radioligand binding studies of bis-(8-isopropyl-isoquinolinium) derivatives as ligands for apamin-sensitive sites on cloned SK2 and SK3 channels.
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.
authors: Laboratory of Medicinal Chemistry and C.I.R.M., University of Liège, 1 Avenue de l'Hôpital (B36), B-4000 Liège 1, Belgium.
authors: Eduard
authors: E
authors: Badarau
authors: Sébastien
authors: S
authors: Dilly
authors: Fabien
authors: F
authors: Dufour
authors: Sylvie
authors: S
authors: Poncin
authors: Vincent
authors: V
authors: Seutin
authors: Jean-François
authors: JF
authors: Liégeois
mesh_terms: D019840:2-Propanol / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001030:Apamin / Q000378:metabolism*; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011869:Radioligand Assay; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D008024:Ligands; D051640:Small-Conductance Calcium-Activated Potassium Channels; C465280:methyl-laudanosine; D001030:Apamin; D019840:2-Propanol