ORBi: Graulich Amaury - Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+- activated K+ channels

Reference : Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolini...


	Document type :	Scientific journals : Article
	Discipline(s) :	Human health sciences : Pharmacy, pharmacology & toxicology Physical, chemical, mathematical & earth Sciences : Chemistry
	To cite this reference:	http://hdl.handle.net/2268/5135

Title :	Synthesis and radioligand binding studies of methoxylated 1,2,3,4-tetrahydroisoquinolinium derivatives as ligands of the apamin-sensitive Ca2+- activated K+ channels
Language :	English
Author, co-author :	Graulich, Amaury [Université de Liège - ULg > > Chimie pharmaceutique >]
	Scuvée-Moreau, Jacqueline [Université de Liège - ULg > Département des sciences cognitives > Neuroscience comportementale et psychopharmacologie expér. >]
	Alleva, Livia [Université de Liège - ULg > > Pharmacologie >]
	Lamy, Cédric [Université de Liège - ULg > > Pharmacologie >]
	Waroux, Olivier [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
	Seutin, Vincent [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
	Liégeois, Jean-François [ > > ]
Publication date :	30-Nov-2006
Journal title :	Journal of Medicinal Chemistry
Publisher :	Amer Chemical Soc
Volume :	49
Issue/season :	24
Pages :	7208-7214
Audience :	International
ISSN :	0022-2623
City :	Washington
Keywords :	[en] Apamin ; Binding ; Amines
	[fr] N-methyl-laudnosine ; N-methyl-noscapine
Abstract :	[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.
Research units :	CNCM
Permalink :	http://hdl.handle.net/2268/5135

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