title: Synthesis of substituted diphenyl sulfones and their structure-activity relationship with the antagonism of 5-НТ6 receptors.
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-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.
authors.affiliation: Department of Organic Chemistry and Department of Molecular Pharmacology, CDRI, 114401 Khimki, Moscow Reg, Russia.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ivachtchenko
authors.forename: Elena
authors.initials: E
authors.lastname: Golovina
authors.forename: Madina
authors.initials: M
authors.lastname: Kadieva
authors.forename: Oleg
authors.initials: O
authors.lastname: Mitkin
authors.forename: Sergei
authors.initials: S
authors.lastname: Tkachenko
authors.forename: Ilya
authors.initials: I
authors.lastname: Okun
mesh_terms: D000595:Amino Acid Sequence; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008969:Molecular Sequence Data; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014162:Transfection
chemical_list: D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; C097216:serotonin 6 receptor