Design of fluorinated 5-HT4R antagonists: Influence of the basicity and lipophilicity toward the 5-HT4R binding affinities |
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Authors: | Clement Q. Fontenelle Zhong Wang Christine Fossey Thomas Cailly Bruno Linclau Frederic Fabis |
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Affiliation: | 1. Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK;2. Normandie Université, France;3. Université de Caen Basse-Normandie, CERMN (EA 4258—FR CNRS 3038 INC3M—SF 4206 ICORE) UFR des Sciences Pharmaceutiques, Bd Becquerel, CS 14032 Caen Cedex 5, France |
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Abstract: | 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. |
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Keywords: | CNS Fluorination Lipophilicity Basicity |
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