title: Design of fluorinated 5-HT(4)R antagonists: influence of the basicity and lipophilicity toward the 5-HT(4)R binding affinities.
abstract: Analogues of potent 5-HT(4)R 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-HT(4)R while maintaining their pharmacological profile and selectivity toward other 5-HT receptors.
authors.affiliation: Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK.
authors.forename: Clement Q
authors.initials: CQ
authors.lastname: Fontenelle
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Christine
authors.initials: C
authors.lastname: Fossey
authors.forename: Thomas
authors.initials: T
authors.lastname: Cailly
authors.forename: Bruno
authors.initials: B
authors.lastname: Linclau
authors.forename: Frederic
authors.initials: F
authors.lastname: Fabis
mesh_terms: D000818:Animals; D015195:Drug Design; D006168:Guinea Pigs; D054879:Halogenation; D006801:Humans; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058832:Serotonin 5-HT4 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D010880:Piperidines; D058832:Serotonin 5-HT4 Receptor Antagonists; D044422:Receptors, Serotonin, 5-HT4; C032727:piperidine
keywords: 5-HT(4); Basicity; CNS; Fluorination; Lipophilicity