Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid

Niels Krogsgaard-Larsen; Claudia Delgar; Karina Koch; Patricia M G E Brown; Charlotte Møller; Liwei Han; Tri Hien Viet Huynh; Stinne Wessel Hansen; Birgitte Nielsen; Derek Bowie; Darryl S Pickering; Jette Sandholm Jensen Kastrup; Karla Andrea Frydenvang; Lennart Bunch

doi:10.1021/acs.jmedchem.6b01516

Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid

Niels Krogsgaard-Larsen, Claudia Delgar, Karina Koch, Patricia M G E Brown, Charlotte Møller, Liwei Han, Tri Hien Viet Huynh, Stinne Wessel Hansen, Birgitte Nielsen, Derek Bowie, Darryl S Pickering, Jette Sandholm Jensen Kastrup, Karla Andrea Frydenvang, Lennart Bunch

3 Citationer (Scopus)

Abstract

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (K_i = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC₅₀ = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	60
Udgave nummer	1
Sider (fra-til)	441-457
Antal sider	17
ISSN	0022-2623
DOI	https://doi.org/10.1021/acs.jmedchem.6b01516
Status	Udgivet - 12 jan. 2017

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10.1021/acs.jmedchem.6b01516

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Citationsformater

Krogsgaard-Larsen, N., Delgar, C., Koch, K., Brown, P. M. G. E., Møller, C., Han, L., Huynh, T. H. V., Hansen, S. W., Nielsen, B., Bowie, D., Pickering, D. S., Kastrup, J. S. J., Frydenvang, K. A., & Bunch, L. (2017). Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid. Journal of Medicinal Chemistry, 60(1), 441-457. https://doi.org/10.1021/acs.jmedchem.6b01516

Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid. / Krogsgaard-Larsen, Niels; Delgar, Claudia; Koch, Karina et al.
I: Journal of Medicinal Chemistry, Bind 60, Nr. 1, 12.01.2017, s. 441-457.

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

Krogsgaard-Larsen, N, Delgar, C, Koch, K, Brown, PMGE, Møller, C, Han, L, Huynh, THV, Hansen, SW, Nielsen, B, Bowie, D, Pickering, DS , Kastrup, JSJ , Frydenvang, KA & Bunch, L 2017, 'Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid', Journal of Medicinal Chemistry, bind 60, nr. 1, s. 441-457. https://doi.org/10.1021/acs.jmedchem.6b01516

Krogsgaard-Larsen N, Delgar C, Koch K, Brown PMGE, Møller C, Han L et al. Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid. Journal of Medicinal Chemistry. 2017 jan. 12;60(1):441-457. doi: 10.1021/acs.jmedchem.6b01516

Krogsgaard-Larsen, Niels ; Delgar, Claudia ; Koch, Karina et al. / Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid. I: Journal of Medicinal Chemistry. 2017 ; Bind 60, Nr. 1. s. 441-457.

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title = "Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid",

abstract = "Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.",

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T1 - Design and Synthesis of a Series of L-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid

AU - Krogsgaard-Larsen, Niels

AU - Delgar, Claudia

AU - Koch, Karina

AU - Brown, Patricia M G E

AU - Møller, Charlotte

AU - Han, Liwei

AU - Huynh, Tri Hien Viet

AU - Hansen, Stinne Wessel

AU - Nielsen, Birgitte

AU - Bowie, Derek

AU - Pickering, Darryl S

AU - Kastrup, Jette Sandholm Jensen

AU - Frydenvang, Karla Andrea

AU - Bunch, Lennart

PY - 2017/1/12

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N2 - Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.

AB - Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.

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