Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists. / Conti, Paola; De Amici, Marco; Grazioso, Giovanni; Roda, Gabriella; Barberis Negra, Federico F; Nielsen, Birgitte; Stensbøl, Tine B; Madsen, Ulf; Bräuner-Osborne, Hans; Frydenvang, Karla Andrea; De Sarro, Giovambattista; Toma, Lucio; De Micheli, Carlo.
In: Journal of Medicinal Chemistry, Vol. 47, No. 27, 30.12.2004, p. 6740-8.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists
AU - Conti, Paola
AU - De Amici, Marco
AU - Grazioso, Giovanni
AU - Roda, Gabriella
AU - Barberis Negra, Federico F
AU - Nielsen, Birgitte
AU - Stensbøl, Tine B
AU - Madsen, Ulf
AU - Bräuner-Osborne, Hans
AU - Frydenvang, Karla Andrea
AU - De Sarro, Giovambattista
AU - Toma, Lucio
AU - De Micheli, Carlo
PY - 2004/12/30
Y1 - 2004/12/30
N2 - The two diastereomeric pairs of acidic amino acids 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid (8A/8B) and 4-(2-amino-2-carboxyethyl)-5,5-dimethyl-4,5-dihydroisoxazole-3-carboxylic acid (10A/10B) were prepared via a strategy based on a 1,3-dipolar cycloaddition. The four amino acids were tested at ionotropic and metabotropic glutamate receptors. None of the compounds was active, neither as agonists nor as antagonists, at 1 mM on metabotropic receptors (mGluR1, -2, -4, and -5 expressed in CHO cell lines). Conversely, the pair of stereoisomers 8A/8B showed a remarkable affinity, antagonist potency, and selectivity for NMDA receptors, when tested on ionotropic glutamate receptors. The affinity of 8A proved to be 5 times higher than that of diastereomer 8B (K(i) values 0.21 and 0.96 microM, respectively). Furthermore, compounds 8A and 8B exhibited a noteworthy anticonvulsant activity in in vivo tests on DBA/2 mice. Derivative 10A was inactive at all ionotropic glutamate receptors, whereas its stereoisomer 10B displayed a seizable binding to both NMDA and AMPA receptors.
AB - The two diastereomeric pairs of acidic amino acids 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid (8A/8B) and 4-(2-amino-2-carboxyethyl)-5,5-dimethyl-4,5-dihydroisoxazole-3-carboxylic acid (10A/10B) were prepared via a strategy based on a 1,3-dipolar cycloaddition. The four amino acids were tested at ionotropic and metabotropic glutamate receptors. None of the compounds was active, neither as agonists nor as antagonists, at 1 mM on metabotropic receptors (mGluR1, -2, -4, and -5 expressed in CHO cell lines). Conversely, the pair of stereoisomers 8A/8B showed a remarkable affinity, antagonist potency, and selectivity for NMDA receptors, when tested on ionotropic glutamate receptors. The affinity of 8A proved to be 5 times higher than that of diastereomer 8B (K(i) values 0.21 and 0.96 microM, respectively). Furthermore, compounds 8A and 8B exhibited a noteworthy anticonvulsant activity in in vivo tests on DBA/2 mice. Derivative 10A was inactive at all ionotropic glutamate receptors, whereas its stereoisomer 10B displayed a seizable binding to both NMDA and AMPA receptors.
KW - Animals
KW - Drug Design
KW - Male
KW - Mice
KW - Mice, Inbred DBA
KW - Molecular Conformation
KW - Rats
KW - Receptors, N-Methyl-D-Aspartate
KW - Structure-Activity Relationship
U2 - 10.1021/jm049409f
DO - 10.1021/jm049409f
M3 - Journal article
C2 - 15615523
VL - 47
SP - 6740
EP - 6748
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 27
ER -
ID: 44758111