Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid. / Krogsgaard-Larsen, Niels; Storgaard, Morten; Møller, Charlotte; Demmer, Charles S; Hansen, Jeanette; Han, Liwei; Monrad, Rune N; Nielsen, Birgitte; Tapken, Daniel; Pickering, Darryl S; Kastrup, Jette S; Frydenvang, Karla; Bunch, Lennart.

In: Journal of Medicinal Chemistry, Vol. 58, No. 15, 2015, p. 6131-50.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Krogsgaard-Larsen, N, Storgaard, M, Møller, C, Demmer, CS, Hansen, J, Han, L, Monrad, RN, Nielsen, B, Tapken, D, Pickering, DS, Kastrup, JS, Frydenvang, K & Bunch, L 2015, 'Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid', Journal of Medicinal Chemistry, vol. 58, no. 15, pp. 6131-50. https://doi.org/10.1021/acs.jmedchem.5b00750

APA

Krogsgaard-Larsen, N., Storgaard, M., Møller, C., Demmer, C. S., Hansen, J., Han, L., ... Bunch, L. (2015). Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid. Journal of Medicinal Chemistry, 58(15), 6131-50. https://doi.org/10.1021/acs.jmedchem.5b00750

Vancouver

Krogsgaard-Larsen N, Storgaard M, Møller C, Demmer CS, Hansen J, Han L et al. Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid. Journal of Medicinal Chemistry. 2015;58(15):6131-50. https://doi.org/10.1021/acs.jmedchem.5b00750

Author

Krogsgaard-Larsen, Niels ; Storgaard, Morten ; Møller, Charlotte ; Demmer, Charles S ; Hansen, Jeanette ; Han, Liwei ; Monrad, Rune N ; Nielsen, Birgitte ; Tapken, Daniel ; Pickering, Darryl S ; Kastrup, Jette S ; Frydenvang, Karla ; Bunch, Lennart. / Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 15. pp. 6131-50.

Bibtex

@article{fb4a89fb69544142834df72249a63860,
title = "Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid",
abstract = "Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 {\AA} resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.",
author = "Niels Krogsgaard-Larsen and Morten Storgaard and Charlotte M{\o}ller and Demmer, {Charles S} and Jeanette Hansen and Liwei Han and Monrad, {Rune N} and Birgitte Nielsen and Daniel Tapken and Pickering, {Darryl S} and Kastrup, {Jette S} and Karla Frydenvang and Lennart Bunch",
year = "2015",
doi = "10.1021/acs.jmedchem.5b00750",
language = "English",
volume = "58",
pages = "6131--50",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "15",

}

RIS

TY - JOUR

T1 - Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

AU - Krogsgaard-Larsen, Niels

AU - Storgaard, Morten

AU - Møller, Charlotte

AU - Demmer, Charles S

AU - Hansen, Jeanette

AU - Han, Liwei

AU - Monrad, Rune N

AU - Nielsen, Birgitte

AU - Tapken, Daniel

AU - Pickering, Darryl S

AU - Kastrup, Jette S

AU - Frydenvang, Karla

AU - Bunch, Lennart

PY - 2015

Y1 - 2015

N2 - Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

AB - Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

U2 - 10.1021/acs.jmedchem.5b00750

DO - 10.1021/acs.jmedchem.5b00750

M3 - Journal article

C2 - 26200741

VL - 58

SP - 6131

EP - 6150

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 15

ER -

ID: 143190912