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 known sulfonyl-containing 5-HT₆R antagonist, showed a strong potency (Ki=1.6 μM). Its derivative with a methylamine substituent, 10g (N-methyl-2-(phenylsulfonyl)aniline), was ∼66-times as active as diphenyl sulfone (Ki=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 (Ki=0.16 nM) to block the serotonin-induced response of HEK-293 cells that were stably transfected with the human recombinant 5-HT₆ receptor.