1. Synthesis, Binding Affinity at Glutamic Acid Receptors, Neuroprotective Effects, and Molecular Modeling Investigation of Novel Dihydroisoxazole Amino Acids
- Author
-
Valentina Vestri, Hans Bräuner-Osborne, Domenico E. Pellegrini-Giampietro, Jan Egebjerg, Giovanni Grazioso, Kasper B. Hansen, Marco De Amici, Birgitte Nielsen, Carlo De Micheli, Francine Acher, Andrea Pinto, Paola Conti, Ulf Madsen, Pauline Sibille, and Gabriella Roda
- Subjects
Models, Molecular ,Patch-Clamp Techniques ,Stereochemistry ,Stereoisomerism ,CHO Cells ,In Vitro Techniques ,Receptors, Metabotropic Glutamate ,Receptors, N-Methyl-D-Aspartate ,Second Messenger Systems ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,Xenopus laevis ,Cricetulus ,Cricetinae ,Drug Discovery ,Animals ,Amino Acids ,Receptor ,Cells, Cultured ,Cerebral Cortex ,chemistry.chemical_classification ,Binding Sites ,Chemistry ,Isoxazoles ,Glutamic acid ,Rats ,Amino acid ,Protein Subunits ,Neuroprotective Agents ,Receptors, Glutamate ,nervous system ,Biochemistry ,Metabotropic glutamate receptor ,Oocytes ,Molecular Medicine ,NMDA receptor ,Female ,Enantiomer ,Ionotropic effect - Abstract
The four stereoisomers of 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid(+)-4, (-)-4, (+)-5, and (-)-5 were prepared by stereoselective synthesis of two pairs of enantiomers, which were subsequently resolved by enzymatic procedures. These four stereoisomers and the four stereoisomers of the bicyclic analogue 5-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylic acid (+)-2, (-)-2, (+)-3, and (-)-3 were tested at ionotropic and metabotropic glutamate receptor subtypes. The most potent NMDA receptor antagonists [(+)-2, (-)-4, and (+)-5] showed a significant neuroprotective effect when tested in an oxygen glucose deprivation (OGD) cell culture test. The same compounds were preliminarily assayed using Xenopus oocytes expressing cloned rat NMDA receptors containing the NR1 subunit in combination with either NR2A, NR2B, NR2C, or NR2D subunit. In this assay, all three derivatives showed high antagonist potency with preference for the NR2A and NR2B subtypes, with derivative (-)-4 behaving as the most potent antagonist. The biological data are discussed on the basis of homology models reported in the literature for NMDA receptors and mGluRs.
- Published
- 2005
- Full Text
- View/download PDF