Bis-(1,2,3,4-tetrahydroisoquinolinium): A Chiral Scaffold for Developing High-Affinity Ligands for SK Channels

Jean François Liégeois, Johan Wouters, Vincent Seutin, Sébastien Dilly

Résultats de recherche: Contribution à un journal/une revueArticle

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 originaleAnglais
journalChemMedChem
Les DOIs
étatPublié - avr. 2014

Empreinte digitale

tetrandrine
Scaffolds
Isomers
Small-Conductance Calcium-Activated Potassium Channels
Tetrahydroisoquinolines
Ligands
Radioligand Assay
Stereoisomerism
Stereochemistry
Assays
Derivatives
1,2,3,4-tetrahydroisoquinoline
1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)

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title = "Bis-(1,2,3,4-tetrahydroisoquinolinium): A Chiral Scaffold for Developing High-Affinity Ligands for SK Channels",
abstract = "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.",
keywords = "Calcium-activated potassium channels, Heterocycles, N-methyltetrandrine, Quaternized nitrogen atoms, Stereochemistry",
author = "Li{\'e}geois, {Jean Fran{\cc}ois} and Johan Wouters and Vincent Seutin and S{\'e}bastien Dilly",
year = "2014",
month = "4",
doi = "10.1002/cmdc.201400028",
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journal = "ChemMedChem",
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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 revueArticle

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

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DO - 10.1002/cmdc.201400028

M3 - Article

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

ER -