title: (Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists.
abstract: 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.
authors: Chemical Research Division and Preclinical Research Division, EGIS Pharmaceuticals Plc, P.O. Box 100, H-1475 Budapest, Hungary. volk.balazs@egis.hu
authors: Balázs
authors: B
authors: Volk
authors: József
authors: J
authors: Barkóczy
authors: Endre
authors: E
authors: Hegedus
authors: Szabolcs
authors: S
authors: Udvari
authors: István
authors: I
authors: Gacsályi
authors: Tibor
authors: T
authors: Mezei
authors: Katalin
authors: K
authors: Pallagi
authors: Hajnalka
authors: H
authors: Kompagne
authors: György
authors: G
authors: Lévay
authors: András
authors: A
authors: Egyed
authors: László G
authors: LG
authors: Hársing
authors: Michael
authors: M
authors: Spedding
authors: Gyula
authors: G
authors: Simig
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
chemical_list: D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor