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Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2006 May 15; Vol. 14 (10), pp. 3405-20. Date of Electronic Publication: 2006 Jan 20. - Publication Year :
- 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), (1R,2S,5R,6R)-2-amino-3-(3,4-dichlorobenzylthio)-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic acid (15at), and (1R,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(i) = 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.
- Subjects :
- Animals
Anti-Anxiety Agents chemistry
Binding, Competitive drug effects
Bridged Bicyclo Compounds pharmacokinetics
Cell Line
Cells, Cultured
Drug Evaluation, Preclinical
Excitatory Amino Acid Agonists chemical synthesis
Excitatory Amino Acid Agonists pharmacology
Excitatory Amino Acid Antagonists pharmacokinetics
Male
Molecular Structure
Rats
Receptors, Metabotropic Glutamate agonists
Receptors, Metabotropic Glutamate metabolism
Structure-Activity Relationship
Bridged Bicyclo Compounds chemical synthesis
Bridged Bicyclo Compounds pharmacology
Excitatory Amino Acid Antagonists chemical synthesis
Excitatory Amino Acid Antagonists pharmacology
Receptors, Metabotropic Glutamate antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0968-0896
- Volume :
- 14
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16431115
- Full Text :
- https://doi.org/10.1016/j.bmc.2005.12.061