Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists

被引:12
|
作者
Yasuhara, A
Sakagami, K
Yoshikawa, R
Chaki, S
Nakamura, M
Nakazato, A
机构
[1] Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama-shi, Saitama, 331-9530
关键词
mGluR2; antagonist; 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acids; synthesis; structure-activity relationship;
D O I
10.1016/j.bmc.2005.12.061
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Chemical modification of the bicyclo[3.1.0]hexane ring C-3 position led to the discovery of 3-alkoxy-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 3-benzylthio-, and 3-benzylamino-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, metabotropic glutamate receptor 2 (mGluR2) antagonists. In particular, 3-(3,4-dichlorobenzyloxy)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15ae), (IR,2S,5R,6R)-2-animo-3-(3,4-dichlorobenzylthio)-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic acid (15at), and (IR,2S,5R,6R)-2-amino-3-(N-(3,4-dichlorobenzylamino))-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic (15ba) showed high affinity for the mGluR2 receptor (15ae: K-1 = 2.51 nM, 15at: K-i = 1.96 nM, and 15ba: K-i = 3.29 nM) and potent antagonist activity for mGluR2 (15ae; IC50 = 34.21 nM, 15at; IC50 = 13.34 nM, and 15ba; IC50 = 35.96 nM). No significant agonist activity for mGluR2 was observed with 15ae, 15at, or 15ba. This paper reports on the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3405 / 3420
页数:16
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