Article (Scientific journals)
Bis-(1,2,3,4-tetrahydroisoquinolinium): a chiral scaffold for developing high affinity ligands for SK channels
Liégeois, Jean-François; Wouters, Johan; Seutin, Vincent et al.
2014In ChemMedChem, 9, p. 737-740
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Keywords :
calcium-activated potassium channel; stereoisomer; affinity
Abstract :
[en] N-Methyl-bis-(1,2,3,4-tetrahydroisoquinolinium) analogues derived from AG525 (1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)) stereoisomers and tetrandrine, a rigid bis-(1,2,3,4-tetrahydroisoquinoline) analogue with an S,S configuration, were synthesized and tested for their affinity for small-conductance calcium-activated potassium channel (SK/KCa2) subtypes using radioligand binding assays. A significant increase in affinity was observed for the quaternized analogues over the parent 1,2,3,4-tetrahydroisoquinoline compounds. Interestingly, the impact of stereochemistry was not the same in the two groups of compounds. For quaternized analogues, affinities of S,S and R,R isomers for SK2 and SK3 channels were similar and in both cases higher than that of the meso derivative. Among the bis-tetrahydroisoquinoline compounds, the S,S isomers exhibited high affinity, while the R,R and meso isomers had similarly lower affinities. Furthermore, the SK2/SK3 selectivity ratio was slightly increased for quaternized analogues. Bis-(1,2,3,4-tetrahydroisoquinolinium) represents a new scaffold for the development of high-affinity ligands for SK channel subtypes
Research center :
Centre Interfacultaire de Recherche du Médicament - CIRM
Disciplines :
Chemistry
Pharmacy, pharmacology & toxicology
Author, co-author :
Liégeois, Jean-François ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Wouters, Johan;  Université de namur
Seutin, Vincent ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Dilly, Sébastien ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Pharmacologie
Language :
English
Title :
Bis-(1,2,3,4-tetrahydroisoquinolinium): a chiral scaffold for developing high affinity ligands for SK channels
Publication date :
2014
Journal title :
ChemMedChem
ISSN :
1860-7179
eISSN :
1860-7187
Publisher :
Wiley - VCH Verlag GmbH & Co., Germany
Volume :
9
Pages :
737-740
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 27 February 2014

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