ORBi: Graulich Amaury - Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers

Reference : Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quater...


	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/2268/6101

Title :	Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers
Language :	English
Author, co-author :	Graulich, Amaury [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
	Lamy, Cédric [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
	Alleva, Livia [Université de Liège - ULg > Département des sciences cognitives > Neuroscience comportementale et psychopharmacologie expér. >]
	Dilly, Sébastien [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
	Chavatte, Philippe [> > > >]
	Wouters, Johan [> > > >]
	Seutin, Vincent [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Pharmacologie >]
	Liégeois, Jean-François [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Publication date :	2008
Journal title :	Bioorganic & Medicinal Chemistry Letters
Volume :	18
Issue/season :	11
Pages :	3440-3445
Audience :	International
ISSN :	0960-894X
Abstract :	[en] So far, small conductance Ca2+-activated K+ channel (SK) blockers mostly consist of quaternary ammonium derivatives or peptides. Due to their physicochemical properties, these blockers are not suitable to study the physiological roles of SK channels in the central nervous system in vivo. Herein, we report the discovery of a chiral bis-tertiary amine with SK blocking properties from chemical modulation of laudanosine. AG525E1 has an affinity for SK channels (K-i = 293 nM) approximately 100-fold higher than the tertiary compound laudanosine (K-i similar to 30 mu M) and similar to the charged compound dequalinium (K-i = 221 nM). AG525E1 equipotently blocks SK1, SK2 and SK3 currents in transfected cell lines. Because of its basic and lipophilic properties, it can reach central SK targets. (c) 2008 Elsevier Ltd. All rights reserved.
Target :	Researchers ; Professionals ; Students
Permalink :	http://hdl.handle.net/2268/6101
DOI :	10.1016/j.bmcl.2008.03.069

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