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

被引：98

作者：

Volk, Balazs ^{[1
]}

Barkoczy, Jozsef ^{[1
]}

Hegedus, Endre ^{[2
]}

Udvari, Szabolcs ^{[2
]}

Gacsalyi, Istvan ^{[2
]}

Mezei, Tibor ^{[1
]}

Pallagi, Katalin ^{[2
]}

Kompagne, Hajnalka ^{[2
]}

Levay, Gyoergy ^{[2
]}

Egyed, Andras ^{[2
]}

Harsing, Laszlo G., Jr. ^{[2
]}

Spedding, Michael ^{[3
]}

Simig, Gyula ^{[1
]}

机构：

[1] EGIS Pharmaceut Plc, Div Chem Res, H-1475 Budapest, Hungary

[2] EGIS Pharmaceut Plc, Preclin Res Div, H-1475 Budapest, Hungary

[3] Inst Rech Servier, F-92150 Suresnes, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 08期

关键词：

D O I：

10.1021/jm070279v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of potent 5-hydroxytryptamine(7) (5-HT(7)) ligands has been synthesized that contain a 1,3-dihydro-2H-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-licands. 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-HT(7) receptor-ligands were estimated by the conflict drinking (Vogel) and the light-dark anxiolytic tests.

引用

页码：2522 / 2532

页数：11

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