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

Design of fluorinated 5-HT4R antagonists: influence of the basicity and lipophilicity toward the 5-HT4R binding affinities
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 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.
cns, 5-ht4, fluorination, lipophilicity, basicity
0968-0896
7529-7538
Fontenelle, Clement Q.
929410b0-7dcb-4c83-a9f7-ef2be8e81fbb
Wang, Zhong
ef9f8b13-c3f0-48d7-b8e2-95b0f757c30a
Fossey, Christine
2c17daf2-57e6-4dba-8ea6-7ecb736ea1ce
Cailly, Thomas
a4af3d53-d8ce-4e15-bae3-dfa55a321ba3
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Fabis, Frederic
492abd67-8b74-467b-97f1-b167faa193c3
Fontenelle, Clement Q.
929410b0-7dcb-4c83-a9f7-ef2be8e81fbb
Wang, Zhong
ef9f8b13-c3f0-48d7-b8e2-95b0f757c30a
Fossey, Christine
2c17daf2-57e6-4dba-8ea6-7ecb736ea1ce
Cailly, Thomas
a4af3d53-d8ce-4e15-bae3-dfa55a321ba3
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Fabis, Frederic
492abd67-8b74-467b-97f1-b167faa193c3

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).

Record type: Article

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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More information

Published date: December 2013
Keywords: cns, 5-ht4, fluorination, lipophilicity, basicity
Organisations: University of Southampton

Identifiers

Local EPrints ID: 359342
URI: http://eprints.soton.ac.uk/id/eprint/359342
ISSN: 0968-0896
PURE UUID: e0d26f3b-9205-4e2a-ad0c-4d29902f5720
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

Catalogue record

Date deposited: 28 Oct 2013 13:14
Last modified: 18 Feb 2021 16:55

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Contributors

Author: Clement Q. Fontenelle
Author: Zhong Wang
Author: Christine Fossey
Author: Thomas Cailly
Author: Bruno Linclau ORCID iD
Author: Frederic Fabis

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