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

TY - JOUR

T1 - Synthesis, binding affinity at glutamic acid receptors, neuroprotective effects, and molecular modeling investigation of novel dihydroisoxazole amino acids

AU - Conti, Paola

AU - De Amici, Marco

AU - Grazioso, Giovanni

AU - Roda, Gabriella

AU - Pinto, Andrea

AU - Hansen, Kasper Bø

AU - Nielsen, Birgitte

AU - Madsen, Ulf

AU - Bräuner-Osborne, Hans

AU - Egebjerg, Jan

AU - Vestri, Valentina

AU - Pellegrini-Giampietro, Domenico E

AU - Sibille, Pauline

AU - Acher, Francine C

AU - De Micheli, Carlo

PY - 2005/10/6

Y1 - 2005/10/6

N2 - 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.

AB - 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.

KW - Amino Acids

KW - Animals

KW - Binding Sites

KW - CHO Cells

KW - Cells, Cultured

KW - Cerebral Cortex

KW - Cricetinae

KW - Cricetulus

KW - Female

KW - Isoxazoles

KW - Mice

KW - Models, Molecular

KW - Neuroprotective Agents

KW - Oocytes

KW - Patch-Clamp Techniques

KW - Protein Subunits

KW - Radioligand Assay

KW - Rats

KW - Receptors, Glutamate

KW - Receptors, Metabotropic Glutamate

KW - Receptors, N-Methyl-D-Aspartate

KW - Second Messenger Systems

KW - Stereoisomerism

KW - Structure-Activity Relationship

KW - Xenopus laevis

U2 - 10.1021/jm0504499

DO - 10.1021/jm0504499

M3 - Journal article

C2 - 16190758

SN - 0022-2623

VL - 48

SP - 6315

EP - 6325

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -