Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists.
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.
Conti
Paola
P
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy.
De Amici
Marco
M
Grazioso
Giovanni
G
Roda
Gabriella
G
Barberis Negra
Federico F
FF
Nielsen
Birgitte
B
Stensbøl
Tine B
TB
Madsen
Ulf
U
Bräuner-Osborne
Hans
H
Frydenvang
Karla
K
De Sarro
Giovambattista
G
Toma
Lucio
L
De Micheli
Carlo
C
D000818:Animals; D015195:Drug Design; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008968:Molecular Conformation; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D016194:Receptors, N-Methyl-D-Aspartate