Synthesis and receptor binding assay of indolin-2-one derivatives as dopamine D4 receptor ligands

Five indolin-2-one derivatives bearing piperazinylbutyl side chains attached to the amide nitrogen were synthesized from 2-indolinone. 1-(4-BromobutyI)-indolin-2-one was reacted with 1-piperazinecarboxaldehyde to form 1-(4-(4-formyl-1-piperazinyl)butyl)indolin-2-one (2). In the presence of H2SO4, the aldehyde moiety was removed from 1-(4-(4-formyl-1-piperazinyl)butyl)indolin-2-one and then 1-(4-(1-piperazinyl)butyl)indolin-2-one (3) was obtained, this compound was reacted with benzaldehyde derivatives to give the target compounds 4 a-e by N-alkylation reaction. The structures of the intermediates and the target compounds were characterized by H-1 NMR, ESI-MS spectra and elemental analyses. In vitro receptor binding assays at D-2, D-3, D-4 receptor subtypes of the target compounds were performed and the five compounds showed selectivity towards D-2-like receptors. Among them, 1-(4-(4-(4-hydroxybenzyl)-1-piperazinyl)butyl) indolin-2-one (4c) exhibited a remarkable affinity and selectivity to D-4 receptor with K-i value of 0.5 nM. The results indicated that 1-(4-(4-(4-hydroxybenzyI)-1- piperazinyl)butyl)indolin-2-one might be a potential dopamine D-4 receptor ligand.