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

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

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; Brown, Patricia M G E; Møller, Charlotte; Han, Liwei; Huynh, Tri Hien Viet; Hansen, Stinne Wessel; Nielsen, Birgitte; Bowie, Derek; Pickering, Darryl S; Kastrup, Jette Sandholm Jensen; Frydenvang, Karla Andrea; Bunch, Lennart.

In: Journal of Medicinal Chemistry, Vol. 60, No. 1, 2017, p. 441-457.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

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, vol. 60, no. 1, pp. 441-457. https://doi.org/10.1021/acs.jmedchem.6b01516

APA

Krogsgaard-Larsen, N., Delgar, C., Koch, K., Brown, P. M. G. E., Møller, C., Han, L., ... 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

Vancouver

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;60(1):441-457. https://doi.org/10.1021/acs.jmedchem.6b01516

Author

Krogsgaard-Larsen, Niels ; Delgar, Claudia ; Koch, Karina ; Brown, Patricia M G E ; Møller, Charlotte ; Han, Liwei ; Huynh, Tri Hien Viet ; Hansen, Stinne Wessel ; Nielsen, Birgitte ; Bowie, Derek ; Pickering, Darryl S ; Kastrup, Jette Sandholm Jensen ; Frydenvang, Karla Andrea ; Bunch, Lennart. / 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. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 1. pp. 441-457.

Bibtex

@article{af5b62bdb8d841fcbe439d927e6f2d9b,
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-carboxy-phenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptor 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.",
author = "Niels Krogsgaard-Larsen and Claudia Delgar and Karina Koch and Brown, {Patricia M G E} and Charlotte M{\o}ller and Liwei Han and Huynh, {Tri Hien Viet} and Hansen, {Stinne Wessel} and Birgitte Nielsen and Derek Bowie and Pickering, {Darryl S} and Kastrup, {Jette Sandholm Jensen} and Frydenvang, {Karla Andrea} and Lennart Bunch",
year = "2017",
doi = "10.1021/acs.jmedchem.6b01516",
language = "English",
volume = "60",
pages = "441--457",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "1",

}

RIS

TY - JOUR

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

Y1 - 2017

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-carboxy-phenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptor 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-carboxy-phenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptor 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.

U2 - 10.1021/acs.jmedchem.6b01516

DO - 10.1021/acs.jmedchem.6b01516

M3 - Journal article

C2 - 28005385

VL - 60

SP - 441

EP - 457

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 1

ER -

ID: 170140162