Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3. / Bunch, Lennart; Nielsen, Birgitte; Jensen, Anders A.; Bräuner-Osborne, Hans.

In: Journal of Medicinal Chemistry, Vol. 49, No. 1, 2006, p. 172-8.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Bunch, L, Nielsen, B, Jensen, AA & Bräuner-Osborne, H 2006, 'Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3', Journal of Medicinal Chemistry, vol. 49, no. 1, pp. 172-8. https://doi.org/10.1021/jm0508336

APA

Bunch, L., Nielsen, B., Jensen, A. A., & Bräuner-Osborne, H. (2006). Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3. Journal of Medicinal Chemistry, 49(1), 172-8. https://doi.org/10.1021/jm0508336

Vancouver

Bunch L, Nielsen B, Jensen AA, Bräuner-Osborne H. Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3. Journal of Medicinal Chemistry. 2006;49(1):172-8. https://doi.org/10.1021/jm0508336

Author

Bunch, Lennart ; Nielsen, Birgitte ; Jensen, Anders A. ; Bräuner-Osborne, Hans. / Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 1. pp. 172-8.

Bibtex

@article{0f7eb9d14720461188c6ea9056fd5c87,
title = "Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3",
abstract = "The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglutaminol, in an enantioselective fashion, in 14 steps. Pharmacological characterization of 1a at human glutamate transporter subtypes 1, 2, and 3 yielded K(i) values of 127, 52, and 46 microM, respectively. Furthermore, binding studies at native ionotropic Glu (iGlu) receptors revealed low affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-preferring iGlu receptors (IC(50) > 100 microM), whereas affinities for the KAIN-preferring iGlu receptors and the N-methyl-d-aspartate (NMDA)-preferring group of iGlu receptors were in the low micromolar range (IC(50) = 14 and 2.9 microM, respectively). At metabotropic Glu receptors (mGluR), EC(50) values for 1a were >1000 microM for mGluR1 and 4, representing group I and III, respectively, and approximately 1000 microM (agonist) for mGluR2, representing group II.",
keywords = "Animals, Bicyclo Compounds, Heterocyclic, Binding Sites, Cell Line, Dicarboxylic Acids, Drug Design, Excitatory Amino Acid Transporter 1, Excitatory Amino Acid Transporter 3, Glutamate Plasma Membrane Transport Proteins, Humans, Models, Molecular, Molecular Conformation, Rats, Receptors, Glutamate, Stereoisomerism, Structure-Activity Relationship",
author = "Lennart Bunch and Birgitte Nielsen and Jensen, {Anders A.} and Hans Br{\"a}uner-Osborne",
year = "2006",
doi = "10.1021/jm0508336",
language = "English",
volume = "49",
pages = "172--8",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "1",

}

RIS

TY - JOUR

T1 - Rational design and enantioselective synthesis of (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid - a novel inhibitor at human glutamate transporter subtypes 1, 2, and 3

AU - Bunch, Lennart

AU - Nielsen, Birgitte

AU - Jensen, Anders A.

AU - Bräuner-Osborne, Hans

PY - 2006

Y1 - 2006

N2 - The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglutaminol, in an enantioselective fashion, in 14 steps. Pharmacological characterization of 1a at human glutamate transporter subtypes 1, 2, and 3 yielded K(i) values of 127, 52, and 46 microM, respectively. Furthermore, binding studies at native ionotropic Glu (iGlu) receptors revealed low affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-preferring iGlu receptors (IC(50) > 100 microM), whereas affinities for the KAIN-preferring iGlu receptors and the N-methyl-d-aspartate (NMDA)-preferring group of iGlu receptors were in the low micromolar range (IC(50) = 14 and 2.9 microM, respectively). At metabotropic Glu receptors (mGluR), EC(50) values for 1a were >1000 microM for mGluR1 and 4, representing group I and III, respectively, and approximately 1000 microM (agonist) for mGluR2, representing group II.

AB - The natural product kainic acid is used as template for the rational design of a novel conformationally restricted (S)-glutamic acid (Glu) analogue, (1R,4S,5R,6S)-3-azabicyclo[3.3.0]octane-4,6-dicarboxylic acid (1a). The target structure 1a was synthesized from commercially available (S)-pyroglutaminol, in an enantioselective fashion, in 14 steps. Pharmacological characterization of 1a at human glutamate transporter subtypes 1, 2, and 3 yielded K(i) values of 127, 52, and 46 microM, respectively. Furthermore, binding studies at native ionotropic Glu (iGlu) receptors revealed low affinity for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-preferring iGlu receptors (IC(50) > 100 microM), whereas affinities for the KAIN-preferring iGlu receptors and the N-methyl-d-aspartate (NMDA)-preferring group of iGlu receptors were in the low micromolar range (IC(50) = 14 and 2.9 microM, respectively). At metabotropic Glu receptors (mGluR), EC(50) values for 1a were >1000 microM for mGluR1 and 4, representing group I and III, respectively, and approximately 1000 microM (agonist) for mGluR2, representing group II.

KW - Animals

KW - Bicyclo Compounds, Heterocyclic

KW - Binding Sites

KW - Cell Line

KW - Dicarboxylic Acids

KW - Drug Design

KW - Excitatory Amino Acid Transporter 1

KW - Excitatory Amino Acid Transporter 3

KW - Glutamate Plasma Membrane Transport Proteins

KW - Humans

KW - Models, Molecular

KW - Molecular Conformation

KW - Rats

KW - Receptors, Glutamate

KW - Stereoisomerism

KW - Structure-Activity Relationship

U2 - 10.1021/jm0508336

DO - 10.1021/jm0508336

M3 - Journal article

C2 - 16392801

VL - 49

SP - 172

EP - 178

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -

ID: 38484728