title: Synthesis and radioligand binding studies of bis-isoquinolinium derivatives as small conductance Ca(2+)-activated K(+) channel blockers.
abstract: Starting from the scaffold of N-methyllaudanosine and N-methylnoscapine, which are known small conductance Ca2+-activated K+ channel blockers, original bis-isoquinolinium derivatives were synthezised and evaluated using binding studies, electrophysiology, and molecular modeling. These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for the channels than dequalinium. The unsubstituted compounds possess a weaker affinity than the analogues having a 6,7-dimethoxy- or a 6,7,8-trimethoxy substitution. The length of the linker has no influence in the alkane derivatives. In relation to the xylene derivatives, the affinities are higher for the ortho and meta isomers. These results are well corroborated by a molecular modeling study. Finally, the most effective compounds have been tested in electrophysiological experiments on midbrain dopaminergic neurons and demonstrate the blocking potential of the apamin-sensitive after-hyperpolarization.
authors.affiliation: Laboratory of Medicinal Chemistry, Drug Research Center, University of Liège, Avenue de l'Hôpital, 1 (B36), B-4000 Liège 1, Belgium. A.Graulich@student.ulg.ac.be
authors.forename: Amaury
authors.initials: A
authors.lastname: Graulich
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dilly
authors.forename: Amaury
authors.initials: A
authors.lastname: Farce
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Scuvée-Moreau
authors.forename: Olivier
authors.initials: O
authors.lastname: Waroux
authors.forename: Cédric
authors.initials: C
authors.lastname: Lamy
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.forename: Vincent
authors.initials: V
authors.lastname: Seutin
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Liégeois
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D004298:Dopamine