Spiro[pyrrolidine-3, 3′-oxindoles] and their indoline analogues as new 5-HT6 receptor chemotypes

Article abstract of DOI:10.3390/molecules22122221

Synthetic derivatives of spiro[pyrrolidinyl-3, 3′-oxindole] alkaloids (coerulescine analogues) were investigated as new ligands for aminergic G-protein coupled receptors (GPCRs). The chemical starting point 2′-phenylspiro[indoline-3, 3′-pyrrolidin]-2-one scaffold was identified by virtual fragment screening utilizing ligand- and structure based methods. As a part of the hit-to-lead optimization a structure-activity relationship analysis was performed to explore the differently substituted 2′-phenyl-derivatives, introducing the phenylsulphonyl pharmacophore and examining the corresponding reduced spiro[pyrrolidine-3, 3′-indoline] scaffold. The optimization process led to ligands with submicromolar affinities towards the 5-HT₆ receptor that might serve as viable leads for further optimization.