Poster (Scientific congresses and symposiums)
Increased affinity of N-Methyl-AG525 stereoisomers for SK2 and SK3 channels
Liégeois, Jean-François; Seutin, Vincent; Dilly, Sébastien
201343th Annual Meeting Neuroscience
 

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Keywords :
Ion channel; Binding; Alzheimer's disease
Abstract :
[en] Small conductance calcium-activated potassium (SK, KCa2) channels represent interesting and challenging targets in medicinal chemistry. So far, the reference ligand is apamin, a peptide used in most published studies including the [125I] analog for binding studies. Nonpeptidic ligands with high affinity have been developed for several years. Currently, different questions remain to be solved. No selective and brain-penetrating agent is available. In addition, replacing [125I]apamin in binding experiments would be also interesting. We have developed different series of compounds initially derived from laudanosine (1). The quaternized derivative, N-methyl-laudanosine (NML), was found to be a weak SK blocker but highly reversible in electrophysiological experiments (2). Then, bis-charged derivatives were synthesized. Potentially brain-penetrating AG525 stereoisomers were obtained and tested for their affinity for SK channels (3). The affinity of one enantiomer, AG525E1, was found to be close to that of dequalinium (Ki ~ 200 nM) while the two other stereoisomers had a lower affinity. Following this study, quaternization of AG525 stereoisomers was carried out and the affinity of these compounds for SK channel subtypes was determined in comparison with that of parent compounds. We observed a significant increase of affinity for SK2 and SK3 channels for the bis-charged N-methyl derivatives as compared to the basic AG525 stereoisomers to. The ratio of selectivity was increased a little in the case of bis-charged N-methyl derivatives. In addition, the influence of stereochemistry was quite different between both groups. For basic AG525 stereoisomers, the S,S-enantiomer (AG525E1) was the most potent while, within bis-charged N-methyl analogues, both enantiomers had higher affinity. Further in silico approaches should permit to explain these results. References: (1) Graulich et al., Bioorg. Med. Chem. 2005, 13, 1201 (2) Scuvée-Moreau et al., J. Pharmacol. Exp. Ther. 2002, 302, 1176 (3) Graulich et al., Bioorg. Med. Chem. Lett., 2008, 18, 3440
Research center :
Giga-Neurosciences and CIRM
Disciplines :
Pharmacy, pharmacology & toxicology
Computer science
Chemistry
Author, co-author :
Liégeois, Jean-François ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Seutin, Vincent ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Dilly, Sébastien ;  Université de Liège - ULiège > GIGA Neurosciences / Pharmacie > Pharmacologie / Chimie pharmaceutique
Language :
English
Title :
Increased affinity of N-Methyl-AG525 stereoisomers for SK2 and SK3 channels
Publication date :
09 November 2013
Number of pages :
A0
Event name :
43th Annual Meeting Neuroscience
Event organizer :
SFN
Event place :
San Diego, United States
Event date :
November, 9-13, 2013
Audience :
International
Name of the research project :
SK channels
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
ULiège FSR - Université de Liège. Fonds spéciaux pour la recherche [BE]
SPW DGO6 - Service Public de Wallonie. Economie, Emploi, Recherche [BE]
Funding number :
SPW DGO6 PPP NEUREDGE convention 816859
Available on ORBi :
since 27 November 2013

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