Premium
Bis‐(1,2,3,4‐tetrahydroisoquinolinium): A Chiral Scaffold for Developing High‐Affinity Ligands for SK Channels
Author(s) -
Liégeois JeanFrançois,
Wouters Johan,
Seutin Vincent,
Dilly Sébastien
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201400028
Subject(s) - chemistry , tetrandrine , affinities , potassium channel , selectivity , stereochemistry , tetrahydroisoquinoline , biophysics , biochemistry , medicine , pathology , biology , catalysis
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/K Ca 2) 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.