Reference : Synthesis and Radioligand Binding Studies of Bis-Isoquinolinium Derivatives as Small ...
Scientific journals : Article
Physical, chemical, mathematical & earth Sciences : Chemistry
Human health sciences : Pharmacy, pharmacology & toxicology
http://hdl.handle.net/2268/2888
Synthesis and Radioligand Binding Studies of Bis-Isoquinolinium Derivatives as Small Conductance Ca(2+)-Activated K(+) Channel Blockers
English
Graulich, Amaury [Université de Liège - ULg > > Chimie pharmaceutique >]
Dilly, Sébastien mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
Farce, Amaury [> > > >]
Scuvée-Moreau, Jacqueline mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie - Département des sciences biomédicales et précliniques >]
Waroux, Olivier [Université de Liège - ULg > > Pharmacologie >]
Lamy, Cédric [Université de Liège - ULg > > Pharmacologie >]
Chavatte, Philippe [> > > >]
Seutin, Vincent mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
Liégeois, Jean-François mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
18-Oct-2007
Journal of Medicinal Chemistry
Amer Chemical Soc
50
21
5070-5075
Yes (verified by ORBi)
International
0022-2623
Washington
[en] Calcium ; potassium ; N-methyllaudanosine
[en] 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.
http://hdl.handle.net/2268/2888

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