Article (Scientific journals)
Synthesis and Radioligand Binding Studies of Bis-Isoquinolinium Derivatives as Small Conductance Ca(2+)-Activated K(+) Channel Blockers
Graulich, Amaury; Dilly, Sébastien; Farce, Amaury et al.
2007In Journal of Medicinal Chemistry, 50 (21), p. 5070-5075
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Keywords :
Calcium; potassium; N-methyllaudanosine
Abstract :
[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.
Disciplines :
Pharmacy, pharmacology & toxicology
Chemistry
Author, co-author :
Graulich, Amaury ;  Université de Liège - ULiège > Chimie pharmaceutique
Dilly, Sébastien ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Farce, Amaury
Scuvée-Moreau, Jacqueline ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie - Département des sciences biomédicales et précliniques
Waroux, Olivier ;  Université de Liège - ULiège > Pharmacologie
Lamy, Cédric ;  Université de Liège - ULiège > Pharmacologie
Chavatte, Philippe
Seutin, Vincent ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Liégeois, Jean-François ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Language :
English
Title :
Synthesis and Radioligand Binding Studies of Bis-Isoquinolinium Derivatives as Small Conductance Ca(2+)-Activated K(+) Channel Blockers
Publication date :
18 October 2007
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
Amer Chemical Soc, Washington, United States - Washington
Volume :
50
Issue :
21
Pages :
5070-5075
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 18 December 2008

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