Synthesis, binding affinity at glutamic acid receptors, neuroprotective effects, and molecular modeling investigation of novel dihydroisoxazole amino acids

Paola Conti, Marco De Amici, Giovanni Grazioso, Gabriella Roda, Andrea Pinto, Kasper B.ø. Hansen, Birgitte Nielsen, Ulf Madsen, Hans Bräuner-Osborne, Jan Egebjerg, Valentina Vestri, Domenico E. Pellegrini-Giampietro, Pauline Sibille, Francine C. Acher, Carlo De Micheli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)6315-6325
Number of pages11
JournalJournal of Medicinal Chemistry
Volume48
Issue number20
DOIs
StatePublished - Oct 6 2005

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