(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists.
Volk B,
Barkóczy J,
Hegedus E,
Udvari S,
Gacsályi I,
Mezei T,
Pallagi K,
Kompagne H,
Lévay G,
Egyed A,
Hársing LG Jr,
Spedding M,
Simig G.
Chemical Research Division and Preclinical Research Division, EGIS Pharmaceuticals Plc, P.O. Box 100, H-1475 Budapest, Hungary. volk.balazs@egis.hu
A series of potent 5-hydroxytryptamine 7 (5-HT 7) ligands has been synthesized that contain a 1,3-dihydro-2 H-indol-2-one (oxindole) skeleton. The binding of these compounds to the 5-HT 7 and 5-HT 1A receptors was measured. Despite the structural similarity of these two serotonin receptor subtypes, several derivatives exhibited a high selectivity to the 5-HT 7 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-HT 7 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-2 H-indol-2-one ( 9e') exhibited selective 5-HT 7 antagonist activity ( K i = 0.79 nM). The in vivo pharmacological potencies of these 5-HT 7 receptor-ligands were estimated by the conflict drinking (Vogel) and the light-dark anxiolytic tests.
PMID: 18361484 [PubMed - indexed for MEDLINE]