Synthesis, Binding Affinity at Glutamic Acid Receptors, Neuroprotective Effects, and Molecular Modeling Investigation of Novel Dihydroisoxazole Amino Acids
| Autor: | 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, Gabriella Roda |
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| Rok vydání: | 2005 |
| Předmět: |
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 |
| Zdroj: | Journal of Medicinal Chemistry. 48:6315-6325 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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