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

Christian Bernard Matthijs Poulie; Anna Alcaide Lopez; Mikkel Poul Krell-Jørgensen; Younes Larsen; Eloi Astier; Walden E. Bjørn-Yoshimoto; Feng Yi; Jed T Syrenne; Morten Storgaard; Birgitte Nielsen; Karla Andrea Frydenvang; Anders A. Jensen; Kasper B Hansen; Darryl S Pickering; Lennart Bunch

doi:10.1021/acschemneuro.9b00205

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

Christian Bernard Matthijs Poulie, Anna Alcaide Lopez, Mikkel Poul Krell-Jørgensen, Younes Larsen, Eloi Astier, Walden E. Bjørn-Yoshimoto, Feng Yi, Jed T Syrenne, Morten Storgaard, Birgitte Nielsen, Karla Andrea Frydenvang, Anders A. Jensen, Kasper B Hansen, Darryl S Pickering, Lennart Bunch^*

^*Corresponding author af dette arbejde

2 Citationer (Scopus)

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 analogues of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores 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 analogues 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, GluK3-preferring (GluK1/GluK3 K_i ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-fold preference as an antagonist for the GluN1/GluN2A receptor (K_i = 0.61 μM) over GluN1/GluN2B-D (K_i = 2.7-62 μM).

Originalsprog	Engelsk
Tidsskrift	A C S Chemical Neuroscience
Vol/bind	10
Udgave nummer	6
Sider (fra-til)	2989-3007
Antal sider	19
ISSN	1948-7193
DOI	https://doi.org/10.1021/acschemneuro.9b00205
Status	Udgivet - 19 jun. 2019

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10.1021/acschemneuro.9b00205

Citationsformater

Poulie, C. B. M., Alcaide Lopez, A., Krell-Jørgensen, M. P., Larsen, Y., Astier, E., Bjørn-Yoshimoto, W. E., Yi, F., Syrenne, J. T., Storgaard, M., Nielsen, B., Frydenvang, K. A., Jensen, A. A., Hansen, K. B., Pickering, D. S., & 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

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 et al.
I: A C S Chemical Neuroscience, Bind 10, Nr. 6, 19.06.2019, s. 2989-3007.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Poulie, CBM, Alcaide Lopez, A, Krell-Jørgensen, MP, Larsen, Y, Astier, E, Bjørn-Yoshimoto, WE, 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, bind 10, nr. 6, s. 2989-3007. https://doi.org/10.1021/acschemneuro.9b00205

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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 analogues of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores 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 analogues 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, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-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 Bj{\o}rn-Yoshimoto, {Walden E.} 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 = jun,

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doi = "10.1021/acschemneuro.9b00205",

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AU - Poulie, Christian Bernard Matthijs

AU - Alcaide Lopez, Anna

AU - Krell-Jørgensen, Mikkel Poul

AU - Larsen, Younes

AU - Astier, Eloi

AU - Bjørn-Yoshimoto, Walden E.

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 analogues of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores 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 analogues 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, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-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 analogues of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores 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 analogues 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, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-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

C2 - 31124660

SN - 1948-7193

VL - 10

SP - 2989

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JO - A C S Chemical Neuroscience

JF - A C S Chemical Neuroscience

IS - 6

ER -

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

Abstract

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