Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists.
2006
Abstract 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 ), (1 R ,2 S ,5 R ,6 R )-2-amino-3-(3,4-dichlorobenzylthio)-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic acid ( 15at ), and (1 R ,2 S ,5 R ,6 R )-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 i = 2.51 nM, 15at : K i = 1.96 nM, and 15ba : K i = 3.29 nM) and potent antagonist activity for mGluR2 ( 15ae ; IC 50 = 34.21 nM, 15at ; IC 50 = 13.34 nM, and 15ba ; IC 50 = 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.
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