title: Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists.
abstract: 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.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.forename: Marco
authors.initials: M
authors.lastname: De Amici
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.forename: Gabriella
authors.initials: G
authors.lastname: Roda
authors.forename: Federico F
authors.initials: FF
authors.lastname: Barberis Negra
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Tine B
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
authors.forename: Lucio
authors.initials: L
authors.lastname: Toma
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
mesh_terms: 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
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate