Design of fluorinated 5-HT4R antagonists: Influence of the basicity and lipophilicity toward the 5-HT4R binding affinities

Analogues of potent 5-HT4R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with de...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-12, Vol.21 (23), p.7529-7538
Main Authors: Fontenelle, Clement Q., Wang, Zhong, Fossey, Christine, Cailly, Thomas, Linclau, Bruno, Fabis, Frederic
Format: Article
Language:English
Subjects:
5-HT4
antagonists
Basicity
binding capacity
Chemical Sciences
CNS
Fluorination
hydrophobicity
Lipophilicity
Medicinal Chemistry
nitrogen
piperidines
receptors
serotonin
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Summary:Analogues of potent 5-HT4R antagonists possessing a fluorinated N-alkyl chain have been synthesized in order to investigate the effect of the resulting change in basicity and lipophilicity on the affinity and selectivity profile. We demonstrate that for this series, the affinity is decreased with decreased basicity of the piperidine’s nitrogen atom. In contrast, the resulting increase in lipophilicity has minimal impact on binding affinity and selectivity. 3,3,3-Trifluoropropyl and 4,4,4-trifluorobutyl derivatives 6d and 6e have shown to bind to the 5-HT4R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.08.061