Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+- activated K+ channels
[en] Several methoxylated 1,2,3,4-tetrahydroisoquinoliniums derived from N-methyl-laudanosine and N-methyl-noscapine were synthesized and evaluated for their affinity for apamin-sensitive binding sites. The quaternary ammonium derivatives have a higher affinity with regard to the tertiary amines. 6,7-Dimethoxy analogues possess a higher affinity than the 6,8- and 7,8- dimethoxy isomers. A 3,4-dimethoxybenzyl or a 2-naphthylmethyl moiety in C-1 position are more favorable than a 3,4-dimethoxyphenethyl group. Smaller groups such as propyl or isobutyl are unfavorable. In 6,7-dimethoxy analogues, increasing the size and lipophilicity with a naphthyl group in the C-1 position leads to a slight increase of affinity, while the same group in the 6,7,8- trimethoxy series is less favorable. The 6,7,8- trimethoxy derivative 3f is the first tertiary amine in the series to possess an affinity close to that of N-methyl-laudanosine and N-methyl-noscapine. Moreover, electrophysiological studies show that the most effective compound 4f blocks the apamin-sensitive afterhyperpolarization in rat dopaminergic neurons.
Scuvée-Moreau, Jacqueline ; Université de Liège - ULiège > Département des sciences cognitives > Neuroscience comportementale et psychopharmacologie expér.
Alleva, Livia ; Université de Liège - ULiège > Pharmacologie
Lamy, Cédric ; Université de Liège - ULiège > Pharmacologie
Waroux, Olivier ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Seutin, Vincent ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+- activated K+ channels
Publication date :
30 November 2006
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
Amer Chemical Soc, Washington, United States - Washington
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