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

Fontenelle, Clement Q., Wang, Zhong, Fossey, Christine, Cailly, Thomas, Linclau, Bruno and Fabis, Frederic (2013) Design of fluorinated 5-HT4R antagonists: influence of the basicity and lipophilicity toward the 5-HT4R binding affinities. Bioorganic & Medicinal Chemistry, 21 (23), 7529-7538. (doi:10.1016/j.bmc.2013.08.061).

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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Contributors

Author: Bruno Linclau

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