Synthesis, Binding Affinity at Glutamic Acid Receptors, Neuroprotective Effects, and Molecular Modeling Investigation of Novel Dihydroisoxazole Amino Acids
Articolo
Data di Pubblicazione:
2005
Citazione:
Synthesis, Binding Affinity at Glutamic Acid Receptors, Neuroprotective Effects, and Molecular Modeling Investigation of Novel Dihydroisoxazole Amino Acids / P. Conti, M. De Amici, G. Grazioso, G. Roda, A. Pinto, K.B. Hansen, B. Nielsen, U. Madsen, H. Brauner Osborne, J. Egebjerg, V. Vestri, D.E. Pellegrini Giampietro, P. Sibille, F.C. Acher, C. De Micheli. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 48:20(2005 Oct 06), pp. 6315-6325. [10.1021/jm0504499]
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-3aHcyclopenta[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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Glutamate ; NMDA ; AMPA ; Dihydroisoxazole
Elenco autori:
P. Conti, M. De Amici, G. Grazioso, G. Roda, A. Pinto, K.B. Hansen, B. Nielsen, U. Madsen, H. Brauner Osborne, J. Egebjerg, V. Vestri, D.E. Pellegrini Giampietro, P. Sibille, F.C. Acher, C. De Micheli
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