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
收藏
页码：1319 / 1328
页数：10
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