Reference : Increased affinity of N-Methyl-AG525 stereoisomers for SK2 and SK3 channels
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Increased affinity of N-Methyl-AG525 stereoisomers for SK2 and SK3 channels
Liégeois, Jean-François mailto [Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique >]
Seutin, Vincent mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie >]
Dilly, Sébastien mailto [Université de Liège - ULiège > GIGA Neurosciences / Pharmacie > Pharmacologie / Chimie pharmaceutique > >]
43th Annual Meeting Neuroscience
November, 9-13, 2013
San Diego
[en] Ion channel ; Binding ; Alzheimer's disease
[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
Giga-Neurosciences and CIRM
Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS) ; Fonds Spéciaux pour la Recherche of the University of Liège (Belgium) ; SPW DGO6 PPP NEUREDGE convention 816859
SK channels
Researchers ; Professionals ; Students{8D2A5BEC-4825-4CD6-9439-B42BB151D1CF}

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