Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[ω-(1H-indol-3-yl)alkyllpiperazines, novel potential Antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition

被引：52

作者：

Smid, P ^{[1
]}

Coolen, HKAC ^{[1
]}

Keizer, HG ^{[1
]}

van Hes, R ^{[1
]}

de Moes, JP ^{[1
]}

den Hartog, AP ^{[1
]}

Stork, B ^{[1
]}

Plekkenpol, RH ^{[1
]}

Niemann, LC ^{[1
]}

Stroomer, CNJ ^{[1
]}

Tulp, MTM ^{[1
]}

van Stuivenberg, HH ^{[1
]}

McCreary, AC ^{[1
]}

Hesselink, MB ^{[1
]}

Herremans, AHJ ^{[1
]}

Kruse, CG ^{[1
]}

机构：

[1] Solvay Pharmaceut Res Labs, NL-1381 CP Weesp, Netherlands

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 22期

关键词：

D O I：

10.1021/jm050148z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D-2 receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D2 receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D2 receptor pharmacophore or the serotonin transporter pharmacophore.

引用

页码：6855 / 6869

页数：15

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