Rigidized 1-aryl sulfonyl tryptamines: Synthesis and pharmacological evaluation as 5-HT6 receptor ligands

A series of N1-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N1-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole derivatives (tryptamine derivatives with rigidized side chain) have been prepared and tested for their binding affinity to 5-HT6 receptor. Several compounds displayed potent binding affinity for the 5-HT6 receptor when tested in in vitro binding assay. The primary SAR indicates that rigidification of dimethylamino alkyl chain at C3 of indole carbon maintains the binding affinity to 5-HT6R. The lead compound N1-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole, 10a (Kb = 0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT and water maze.

Graphical abstractDesign, synthesis, SAR, pharmacokinetic and pharmacological profile of a series of N1-arylsulfonyl-3-pyrrolidinyl indoles as potent and selective 5-HT6R antagonists was presented. The lead compound N1-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole, 10a (Kb = 0.1 nM) was active in animal models of cognition.Figure optionsDownload full-size imageDownload as PowerPoint slide