Design and Synthesis of 2,3-trans-Proline Analogs as Ligands for the Ionotropic Glutamate Receptors and the Excitatory Amino Acid Transporters

Research output: Contribution to journalJournal articleResearchpeer-review

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Design and Synthesis of 2,3-trans-Proline Analogs as Ligands for the Ionotropic Glutamate Receptors and the Excitatory Amino Acid Transporters. / Poulie, Christian Bernard Matthijs; Alcaide Lopez, Anna; Krell-Jørgensen, Mikkel Poul; Larsen, Younes; Astier, Eloi; Bjørn-Yoshimoto, Walden; Yi, Feng; Syrenne, Jed T; Storgaard, Morten; Nielsen, Birgitte; Frydenvang, Karla Andrea; Jensen, Anders A.; Hansen, Kasper B; Pickering, Darryl S; Bunch, Lennart.

In: A C S Chemical Neuroscience, Vol. 10, No. 6, 19.06.2019, p. 2989-3007.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Poulie, CBM, Alcaide Lopez, A, Krell-Jørgensen, MP, Larsen, Y, Astier, E, Bjørn-Yoshimoto, W, Yi, F, Syrenne, JT, Storgaard, M, Nielsen, B, Frydenvang, KA, Jensen, AA, Hansen, KB, Pickering, DS & Bunch, L 2019, 'Design and Synthesis of 2,3-trans-Proline Analogs as Ligands for the Ionotropic Glutamate Receptors and the Excitatory Amino Acid Transporters', A C S Chemical Neuroscience, vol. 10, no. 6, pp. 2989-3007. https://doi.org/10.1021/acschemneuro.9b00205

APA

Poulie, C. B. M., Alcaide Lopez, A., Krell-Jørgensen, M. P., Larsen, Y., Astier, E., Bjørn-Yoshimoto, W., ... Bunch, L. (2019). Design and Synthesis of 2,3-trans-Proline Analogs as Ligands for the Ionotropic Glutamate Receptors and the Excitatory Amino Acid Transporters. A C S Chemical Neuroscience, 10(6), 2989-3007. https://doi.org/10.1021/acschemneuro.9b00205

Vancouver

Poulie CBM, Alcaide Lopez A, Krell-Jørgensen MP, Larsen Y, Astier E, Bjørn-Yoshimoto W et al. Design and Synthesis of 2,3-trans-Proline Analogs as Ligands for the Ionotropic Glutamate Receptors and the Excitatory Amino Acid Transporters. A C S Chemical Neuroscience. 2019 Jun 19;10(6):2989-3007. https://doi.org/10.1021/acschemneuro.9b00205

Author

Poulie, Christian Bernard Matthijs ; Alcaide Lopez, Anna ; Krell-Jørgensen, Mikkel Poul ; Larsen, Younes ; Astier, Eloi ; Bjørn-Yoshimoto, Walden ; Yi, Feng ; Syrenne, Jed T ; Storgaard, Morten ; Nielsen, Birgitte ; Frydenvang, Karla Andrea ; Jensen, Anders A. ; Hansen, Kasper B ; Pickering, Darryl S ; Bunch, Lennart. / Design and Synthesis of 2,3-trans-Proline Analogs as Ligands for the Ionotropic Glutamate Receptors and the Excitatory Amino Acid Transporters. In: A C S Chemical Neuroscience. 2019 ; Vol. 10, No. 6. pp. 2989-3007.

Bibtex

@article{b6ff0b5890234f3d8bb7d129e4812131,
title = "Design and Synthesis of 2,3-trans-Proline Analogs as Ligands for the Ionotropic Glutamate Receptors and the Excitatory Amino Acid Transporters",
abstract = "Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogs of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explore the effect of introducing a substituent on the ε-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogs of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies several new ligands emerged, exemplified by triazole 3p-d1, a GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4- to 100-fold preference as an antagonist for the GluN1/GluN2A receptor (Ki = 0.61 μM) over GluN1/GluN2B-D (Ki = 2.7-62 μM).",
author = "Poulie, {Christian Bernard Matthijs} and {Alcaide Lopez}, Anna and Krell-J{\o}rgensen, {Mikkel Poul} and Younes Larsen and Eloi Astier and Walden Bj{\o}rn-Yoshimoto and Feng Yi and Syrenne, {Jed T} and Morten Storgaard and Birgitte Nielsen and Frydenvang, {Karla Andrea} and Jensen, {Anders A.} and Hansen, {Kasper B} and Pickering, {Darryl S} and Lennart Bunch",
year = "2019",
month = "6",
day = "19",
doi = "10.1021/acschemneuro.9b00205",
language = "English",
volume = "10",
pages = "2989--3007",
journal = "A C S Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "6",

}

RIS

TY - JOUR

T1 - Design and Synthesis of 2,3-trans-Proline Analogs as Ligands for the Ionotropic Glutamate Receptors and the Excitatory Amino Acid Transporters

AU - Poulie, Christian Bernard Matthijs

AU - Alcaide Lopez, Anna

AU - Krell-Jørgensen, Mikkel Poul

AU - Larsen, Younes

AU - Astier, Eloi

AU - Bjørn-Yoshimoto, Walden

AU - Yi, Feng

AU - Syrenne, Jed T

AU - Storgaard, Morten

AU - Nielsen, Birgitte

AU - Frydenvang, Karla Andrea

AU - Jensen, Anders A.

AU - Hansen, Kasper B

AU - Pickering, Darryl S

AU - Bunch, Lennart

PY - 2019/6/19

Y1 - 2019/6/19

N2 - Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogs of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explore the effect of introducing a substituent on the ε-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogs of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies several new ligands emerged, exemplified by triazole 3p-d1, a GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4- to 100-fold preference as an antagonist for the GluN1/GluN2A receptor (Ki = 0.61 μM) over GluN1/GluN2B-D (Ki = 2.7-62 μM).

AB - Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogs of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explore the effect of introducing a substituent on the ε-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogs of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies several new ligands emerged, exemplified by triazole 3p-d1, a GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4- to 100-fold preference as an antagonist for the GluN1/GluN2A receptor (Ki = 0.61 μM) over GluN1/GluN2B-D (Ki = 2.7-62 μM).

U2 - 10.1021/acschemneuro.9b00205

DO - 10.1021/acschemneuro.9b00205

M3 - Journal article

VL - 10

SP - 2989

EP - 3007

JO - A C S Chemical Neuroscience

JF - A C S Chemical Neuroscience

SN - 1948-7193

IS - 6

ER -

ID: 218311189