ORBi: Dilly Sébastien - Molecular modelling study of bis-isoquinolinium derivatives as small conductance Ca2+

Reference : Molecular modelling study of bis-isoquinolinium derivatives as small conductance Ca2+ - ...


	Document type :	Scientific congresses and symposiums : Poster
	Discipline(s) :	Engineering, computing & technology : Computer science Human health sciences : Pharmacy, pharmacology & toxicology
	To cite this reference:	http://hdl.handle.net/2268/84154

Title :	Molecular modelling study of bis-isoquinolinium derivatives as small conductance Ca2+ - activated K+ channel blockers
Language :	English
Author, co-author :	Dilly, Sébastien [Université de Liège - ULg > Département de pharmacie / Giga-Neurosciences > Chimie pharmaceutique / Pharmacologie > >]
	Graulich, Amaury [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique > >]
	Chavatte, Philippe [Université Nord de France > Faculté des Sciences Pharmaceutiques et Biologiques > Laboratoire de Chimie Thérapeutique > >]
	Seutin, Vincent [Université de Liège - ULg > Giga-Neurosciences > Pharmacologie > >]
	Liégeois, Jean-François [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique > >]
Publication date :	30-May-2008
On invitation :	No
Audience :	International
Event name :	22èmes journées franco-belges de pharmacochimie
Event date :	du 28 au 30 mai 2008
Event organizer :	CERMN, Université de Caen Basse Normandie
Event place (city) :	Caen
Event country :	France
Abstract :	[en] Small conductance calcium-activated potassium channels (SK) are widely expressed throughout the central nervous system and the periphery. Three subtypes of SK channels have been identified so far in different parts of the brain. Activation of SK channels by a rise in intracellular calcium leads to the hyperpolarisation of the membrane, hence reducing cell excitability. Blocking the SK channels might be beneficial for the treatment of depression, Parkinson’s disease and cognitive disorders. In this context, starting from the scaffold of N-methyl-laudanosine (NML) which is a known SK channel blocker (Scuvée-Moreau et al., 2002), a series of original bis-isoquinolinium derivatives were synthezised and evaluated for their affinity on the apamin-sensitive sites (Graulich et al., 2007). These quaternary compounds are powerful blockers, and the most active ones have 10 times more affinity for SK channels than dequalinium. Based on a conformational analysis, a molecular modeling study was also performed. The heads of the various conformational families were compared to a pharmacophoric model previously described (Dilly et al., 2005). The in silico results are well correlated by the in vitro binding studies. Firstly, a 6,7-dimethoxy or a 6,7,8-trimethoxy substitution is shown to be favourable. Secondly, although the length of the linker has no significant influence in the alkane derivatives, the ortho and meta linkers lead to more favourable conformations than the para linker in the xylene derivatives.
Research units :	Giga-Neurosciences, Laboratoire de pharmacologie ; Département de pharmacie, Laboratoire de chimie pharmaceutique
Funders :	Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS ; Université de Liège
Target :	Researchers ; Professionals ; Students
Permalink :	http://hdl.handle.net/2268/84154
Other URL :	http://www.cermn.unicaen.fr/congres_2008/book.pdf

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