Synthesis of Dihydrofuroaporphine Derivatives: Identification of a Potent and Selective Serotonin 5-HT1A Receptor Agonist

被引：36

作者：

Liu, Zhili ^{[2
]}

Zhang, Hai ^{[1
]}

Ye, Na ^{[2
]}

Zhang, Jing ^{[2
]}

Wu, QianQian ^{[1
]}

Sun, Peihua ^{[1
]}

Li, Linyong ^{[1
]}

Zhen, Xuechu ^{[1
]}

Zhang, Ao ^{[2
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Neuropharmacol Lab, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, SOMCL, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 03期

基金：

美国国家科学基金会;

关键词：

VENTRAL TEGMENTAL AREA; NIGRAL DOPAMINE NEURONS; ELEVATED PLUS-MAZE; (R)-APORPHINES SYNTHESIS; PARKINSONS-DISEASE; RAPHE NUCLEUS; RAT; PHARMACOLOGY; ANXIETY; COMPLICATIONS;

D O I：

10.1021/jm9015763

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT1A receptor with K-i values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [S-35]GTP gamma S function assays on 5-HT1A receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT1A receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.

引用

页码：1319 / 1328

页数：10

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