(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists

A series of potent 5-hydroxytryptamine7 (5-HT7) ligands has been synthesized that contain a 1,3-dihydro-2H-indol-2-one (oxindole) skeleton. The binding of these compounds to the 5-HT7 and 5-HT1A receptors was measured. Despite the structural similarity of these two serotonin receptor subtypes, several derivatives exhibited a high selectivity to the 5-HT7 receptor. According to the structure–activity relationship observations, compounds unsubstituted at the oxindole nitrogen atom and containing a tetramethylene spacer between the oxindole skeleton and the basic nitrogen atom are the most potent ligands. Concerning the basic group, besides the moieties of the 4-phenylpiperazine type, halophenyl-1,2,3,6-tetrahydropyridines also proved to be 5-HT7 receptor–ligands. Because of halogen substitution on the aromatic rings, good metabolic stability could be achieved. A representative of the family, 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one (9e′) exhibited selective...