N-methyl-D-aspartic acid receptor agonists: resolution, absolute stereochemistry, and pharmacology of the enantiomers of 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

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Standard

N-methyl-D-aspartic acid receptor agonists : resolution, absolute stereochemistry, and pharmacology of the enantiomers of 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid. / Madsen, U; Frydenvang, Karla Andrea; Ebert, B; Johansen, T N; Brehm, L; Krogsgaard-Larsen, P.

In: Journal of Medicinal Chemistry, Vol. 39, No. 1, 1996, p. 183-90.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Madsen, U, Frydenvang, KA, Ebert, B, Johansen, TN, Brehm, L & Krogsgaard-Larsen, P 1996, 'N-methyl-D-aspartic acid receptor agonists: resolution, absolute stereochemistry, and pharmacology of the enantiomers of 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid', Journal of Medicinal Chemistry, vol. 39, no. 1, pp. 183-90. https://doi.org/10.1021/jm950393q

APA

Madsen, U., Frydenvang, K. A., Ebert, B., Johansen, T. N., Brehm, L., & Krogsgaard-Larsen, P. (1996). N-methyl-D-aspartic acid receptor agonists: resolution, absolute stereochemistry, and pharmacology of the enantiomers of 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid. Journal of Medicinal Chemistry, 39(1), 183-90. https://doi.org/10.1021/jm950393q

Vancouver

Madsen U, Frydenvang KA, Ebert B, Johansen TN, Brehm L, Krogsgaard-Larsen P. N-methyl-D-aspartic acid receptor agonists: resolution, absolute stereochemistry, and pharmacology of the enantiomers of 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid. Journal of Medicinal Chemistry. 1996;39(1):183-90. https://doi.org/10.1021/jm950393q

Author

Madsen, U ; Frydenvang, Karla Andrea ; Ebert, B ; Johansen, T N ; Brehm, L ; Krogsgaard-Larsen, P. / N-methyl-D-aspartic acid receptor agonists : resolution, absolute stereochemistry, and pharmacology of the enantiomers of 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid. In: Journal of Medicinal Chemistry. 1996 ; Vol. 39, No. 1. pp. 183-90.

Bibtex

@article{095dd75f31764866be468a908bed97aa,
title = "N-methyl-D-aspartic acid receptor agonists: resolution, absolute stereochemistry, and pharmacology of the enantiomers of 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid",
abstract = "(R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-D-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi {"}four-component condensation{"} method, the two diastereomers (2R)- and (2S)-2-[3-(benzyloxy)-5-methyl-4-isoxazolyl]N-tert-butyl-2- [N-[(S)-1-phenylethyl]benzamido]-acetamide (16 and 17, respectively) were synthesized and separated chromatographically. The absolute stereochemistry of 16 was confirmed by an X-ray analysis. Deprotection of these intermediates did, however, provide (R)- (8) and (S)- (9) AMAA, respectively, in extensively racemized forms. N-BOC-protected (R,S)-AMAA (21) was successfully resolved via diastereomeric salt formation using cinchonidine. The stereochemical purity and stability of 8 and 9 obtained via this resolution were determined using chiral HPLC. (R)-AMAA (8) showed peak affinity for [3H]AMPA receptor sites (IC50 = 72 +/- 13 microM) and was shown to be a more potent inhibitor of [3H]CPP binding (IC50 = 3.7 +/- 1.5 microM) than (S)-AMAA (9) (IC50 = 61 +/- 6.4 microM). Neither enantiomer of AMAA affected [3H]kainic acid receptor binding significantly. In electrophysiological studies using rat brain tissue, 8 (EC50 = 7.3 +/- 0.3 microM) was 1 order of magnitude more potent than 9 (EC50 = 75 +/- 9 microM) as an NMDA receptor agonist.",
keywords = "Acetic Acids, Animals, Cerebral Cortex, Chromatography, High Pressure Liquid, Crystallography, X-Ray, Electrophysiology, Excitatory Amino Acid Agonists, Hydrogen Bonding, Isoxazoles, Molecular Structure, Rats, Receptors, AMPA, Receptors, Kainic Acid, Receptors, N-Methyl-D-Aspartate, Stereoisomerism",
author = "U Madsen and Frydenvang, {Karla Andrea} and B Ebert and Johansen, {T N} and L Brehm and P Krogsgaard-Larsen",
year = "1996",
doi = "10.1021/jm950393q",
language = "English",
volume = "39",
pages = "183--90",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "1",

}

RIS

TY - JOUR

T1 - N-methyl-D-aspartic acid receptor agonists

T2 - resolution, absolute stereochemistry, and pharmacology of the enantiomers of 2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid

AU - Madsen, U

AU - Frydenvang, Karla Andrea

AU - Ebert, B

AU - Johansen, T N

AU - Brehm, L

AU - Krogsgaard-Larsen, P

PY - 1996

Y1 - 1996

N2 - (R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-D-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi "four-component condensation" method, the two diastereomers (2R)- and (2S)-2-[3-(benzyloxy)-5-methyl-4-isoxazolyl]N-tert-butyl-2- [N-[(S)-1-phenylethyl]benzamido]-acetamide (16 and 17, respectively) were synthesized and separated chromatographically. The absolute stereochemistry of 16 was confirmed by an X-ray analysis. Deprotection of these intermediates did, however, provide (R)- (8) and (S)- (9) AMAA, respectively, in extensively racemized forms. N-BOC-protected (R,S)-AMAA (21) was successfully resolved via diastereomeric salt formation using cinchonidine. The stereochemical purity and stability of 8 and 9 obtained via this resolution were determined using chiral HPLC. (R)-AMAA (8) showed peak affinity for [3H]AMPA receptor sites (IC50 = 72 +/- 13 microM) and was shown to be a more potent inhibitor of [3H]CPP binding (IC50 = 3.7 +/- 1.5 microM) than (S)-AMAA (9) (IC50 = 61 +/- 6.4 microM). Neither enantiomer of AMAA affected [3H]kainic acid receptor binding significantly. In electrophysiological studies using rat brain tissue, 8 (EC50 = 7.3 +/- 0.3 microM) was 1 order of magnitude more potent than 9 (EC50 = 75 +/- 9 microM) as an NMDA receptor agonist.

AB - (R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-D-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi "four-component condensation" method, the two diastereomers (2R)- and (2S)-2-[3-(benzyloxy)-5-methyl-4-isoxazolyl]N-tert-butyl-2- [N-[(S)-1-phenylethyl]benzamido]-acetamide (16 and 17, respectively) were synthesized and separated chromatographically. The absolute stereochemistry of 16 was confirmed by an X-ray analysis. Deprotection of these intermediates did, however, provide (R)- (8) and (S)- (9) AMAA, respectively, in extensively racemized forms. N-BOC-protected (R,S)-AMAA (21) was successfully resolved via diastereomeric salt formation using cinchonidine. The stereochemical purity and stability of 8 and 9 obtained via this resolution were determined using chiral HPLC. (R)-AMAA (8) showed peak affinity for [3H]AMPA receptor sites (IC50 = 72 +/- 13 microM) and was shown to be a more potent inhibitor of [3H]CPP binding (IC50 = 3.7 +/- 1.5 microM) than (S)-AMAA (9) (IC50 = 61 +/- 6.4 microM). Neither enantiomer of AMAA affected [3H]kainic acid receptor binding significantly. In electrophysiological studies using rat brain tissue, 8 (EC50 = 7.3 +/- 0.3 microM) was 1 order of magnitude more potent than 9 (EC50 = 75 +/- 9 microM) as an NMDA receptor agonist.

KW - Acetic Acids

KW - Animals

KW - Cerebral Cortex

KW - Chromatography, High Pressure Liquid

KW - Crystallography, X-Ray

KW - Electrophysiology

KW - Excitatory Amino Acid Agonists

KW - Hydrogen Bonding

KW - Isoxazoles

KW - Molecular Structure

KW - Rats

KW - Receptors, AMPA

KW - Receptors, Kainic Acid

KW - Receptors, N-Methyl-D-Aspartate

KW - Stereoisomerism

U2 - 10.1021/jm950393q

DO - 10.1021/jm950393q

M3 - Journal article

VL - 39

SP - 183

EP - 190

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -

ID: 40372555