(Phenylpiperazinyl-butyl)oxindoles as Selective 5-HT7 Receptor Antagonists

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• 作者：Balá ; zs Volk ; Jó ; zsef Barkó ; czy ; Endre Hegedus ; Szabolcs Udvari ; Istvá ; n Gacsá ; lyi ; Tibor Mezei ; Katalin Pallagi ; Hajnalka Kompagne ; Gy&#xf6 ; rgy Lé ; vay ; Andrá ; s Egyed ; L&#x
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 24, 2008
• 年：2008
• 卷：51
• 期：8
• 页码：2522 - 2532
• 全文大小：256K
• 年卷期：v.51,no.8(April 24, 2008)
• ISSN：1520-4804

文摘

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-HT_1A 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 5-HT₇ antagonist activity (K_i = 0.79 nM). The in vivo pharmacological potencies of these 5-HT₇ receptor–ligands were estimated by the conflict drinking (Vogel) and the light−dark anxiolytic tests.