Rigidized 1-aryl sulfonyl tryptamines: Synthesis and pharmacological evaluation as 5-HT sub(6 receptor ligands)

A series of N sub(1-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N) sub(1)-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-ind ole derivatives (tryptamine derivatives with rigidized side chain) have been prepared and tested for their binding affinity to 5-HT sub(6 receptor. Several compounds displayed potent binding affinity for the 5-HT) sub(6) receptor when tested in in vitro binding assay. The primary SAR indicates that rigidification of dimethylamino alkyl chain at C sub(3 of indole carbon maintains the binding affinity to 5-HT) sub(6)R. The lead compound N sub(1-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol- 3-yl)-1H-indole, 10a (K) sub(b) = 0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT and water maze.