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 Citations (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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	1
Pages (from-to)	441-457
Number of pages	17
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01516
Publication status	Published - 12 Jan 2017

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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.
In: Journal of Medicinal Chemistry, Vol. 60, No. 1, 12.01.2017, p. 441-457.

Research output: Contribution to journal › Journal article › Research › 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, vol. 60, no. 1, pp. 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. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 1. pp. 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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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

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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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