Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Journal of Medicinal Chemistry |
Volume | 47 |
Issue number | 27 |
Pages (from-to) | 6740-8 |
Number of pages | 9 |
ISSN | 0022-2623 |
DOIs | |
Publication status | Published - 30 Dec 2004 |
- Animals, Drug Design, Male, Mice, Mice, Inbred DBA, Molecular Conformation, Rats, Receptors, N-Methyl-D-Aspartate, Structure-Activity Relationship
Research areas
ID: 44758111