Synthesis of substituted diphenyl sulfones and their structure–activity relationship with the antagonism of 5-НТ6 receptors

2013 
Abstract 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-HT 6 receptor were assessed in a cell-based functional assay. Diphenyl sulfone 10a , in spite of being the smallest and simplest known sulfonyl-containing 5-HT 6 R antagonist, showed a strong potency ( K i  = 1.6 μM). Its derivative with a methylamine substituent, 10g ( N -methyl-2-(phenylsulfonyl)aniline), was ∼66-times as active as diphenyl sulfone ( K i  = 24.3 nM). 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 ( K i  = 0.16 nM) to block the serotonin-induced response of HEK-293 cells that were stably transfected with the human recombinant 5-HT 6 receptor.
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