Synthesis of substituted diphenyl sulfones and their structure–activity relationship with the antagonism of 5-НТ6 receptors
Substituted diphenyl sulfones (10a–n) were synthesised, and the structures were confirmed by NMR, LC–MS and X-ray crystallography. Their antagonistic activities towards 5-HT6 receptor were assessed in a cell-based functional assay. Diphenyl sulfone 10a, in spite of being the smallest and simplest kn...
Gespeichert in:
Veröffentlicht in: | Bioorganic & medicinal chemistry 2013-08, Vol.21 (15), p.4614-4627 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Substituted diphenyl sulfones (10a–n) were synthesised, and the structures were confirmed by NMR, LC–MS and X-ray crystallography. Their antagonistic activities towards 5-HT6 receptor were assessed in a cell-based functional assay. Diphenyl sulfone 10a, in spite of being the smallest and simplest known sulfonyl-containing 5-HT6R antagonist, showed a strong potency (Ki=1.6μM). Its derivative with a methylamine substituent, 10g (N-methyl-2-(phenylsulfonyl)aniline), was ∼66-times as active as diphenyl sulfone (Ki=24.3nM). Addition of a piperazinyl moiety in the para-position relative to the sulfonyl group in compound 10m (N-methyl-2-(phenylsulfonyl)-5-piperazin-1-ylaniline) led to a further 150-fold increase in potency (Ki=0.16nM) to block the serotonin-induced response of HEK-293 cells that were stably transfected with the human recombinant 5-HT6 receptor. |
---|---|
ISSN: | 0968-0896 1464-3391 |
DOI: | 10.1016/j.bmc.2013.05.040 |