Résumé
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.
| langue originale | Anglais |
|---|---|
| journal | ChemMedChem |
| Les DOIs | |
| état | Publié - avr. 2014 |
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Bis-(1,2,3,4-tetrahydroisoquinolinium): A Chiral Scaffold for Developing High-Affinity Ligands for SK Channels. / Liégeois, Jean François; Wouters, Johan; Seutin, Vincent; Dilly, Sébastien.
Dans: ChemMedChem, 04.2014.Résultats de recherche: Contribution à un journal/une revue › Article
TY - JOUR
T1 - Bis-(1,2,3,4-tetrahydroisoquinolinium): A Chiral Scaffold for Developing High-Affinity Ligands for SK Channels
AU - Liégeois, Jean François
AU - Wouters, Johan
AU - Seutin, Vincent
AU - Dilly, Sébastien
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - Calcium-activated potassium channels
KW - Heterocycles
KW - N-methyltetrandrine
KW - Quaternized nitrogen atoms
KW - Stereochemistry
UR - http://www.scopus.com/inward/record.url?scp=84894695883&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201400028
DO - 10.1002/cmdc.201400028
M3 - Article
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
ER -