Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists

Paola Conti; Marco De Amici; Giovanni Grazioso; Gabriella Roda; Federico F Barberis Negra; Birgitte Nielsen; Tine B Stensbøl; Ulf Madsen; Hans Bräuner-Osborne; Karla Andrea Frydenvang; Giovambattista De Sarro; Lucio Toma; Carlo De Micheli

doi:10.1021/jm049409f

Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists

Paola Conti, Marco De Amici, Giovanni Grazioso, Gabriella Roda, Federico F Barberis Negra, Birgitte Nielsen, Tine B Stensbøl, Ulf Madsen, Hans Bräuner-Osborne, Karla Andrea Frydenvang, Giovambattista De Sarro, Lucio Toma, Carlo De Micheli

20 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	47
Udgave nummer	27
Sider (fra-til)	6740-8
Antal sider	9
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm049409f
Status	Udgivet - 30 dec. 2004

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10.1021/jm049409f

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Conti, P., De Amici, M., Grazioso, G., Roda, G., Barberis Negra, F. F., Nielsen, B., Stensbøl, T. B., Madsen, U., Bräuner-Osborne, H., Frydenvang, K. A., De Sarro, G., Toma, L., & De Micheli, C. (2004). Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists. Journal of Medicinal Chemistry, 47(27), 6740-8. https://doi.org/10.1021/jm049409f

Conti, P, De Amici, M, Grazioso, G, Roda, G, Barberis Negra, FF, Nielsen, B, Stensbøl, TB, Madsen, U , Bräuner-Osborne, H , Frydenvang, KA, De Sarro, G, Toma, L & De Micheli, C 2004, 'Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists', Journal of Medicinal Chemistry, bind 47, nr. 27, s. 6740-8. https://doi.org/10.1021/jm049409f

@article{92d9f441ec024a7585a016ab308ada85,

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.",

keywords = "Animals, Drug Design, Male, Mice, Mice, Inbred DBA, Molecular Conformation, Rats, Receptors, N-Methyl-D-Aspartate, Structure-Activity Relationship",

author = "Paola Conti and {De Amici}, Marco and Giovanni Grazioso and Gabriella Roda and {Barberis Negra}, {Federico F} and Birgitte Nielsen and Stensb{\o}l, {Tine B} and Ulf Madsen and Hans Br{\"a}uner-Osborne and Frydenvang, {Karla Andrea} and {De Sarro}, Giovambattista and Lucio Toma and {De Micheli}, Carlo",

year = "2004",

month = dec,

day = "30",

doi = "10.1021/jm049409f",

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journal = "Journal of Medicinal Chemistry",

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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

SN - 0022-2623

VL - 47

SP - 6740

EP - 6748

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 27

ER -

Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists

Abstract

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