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

Niels Krogsgaard-Larsen; Morten Storgaard; Charlotte Møller; Charles S Demmer; Jeanette Hansen; Liwei Han; Rune N Monrad; Birgitte Nielsen; Daniel Tapken; Darryl S Pickering; Jette S Kastrup; Karla Frydenvang; Lennart Bunch

doi:10.1021/acs.jmedchem.5b00750

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

Niels Krogsgaard-Larsen, Morten Storgaard, Charlotte Møller, Charles S Demmer, Jeanette Hansen, Liwei Han, Rune N Monrad, Birgitte Nielsen, Daniel Tapken, Darryl S Pickering, Jette S Kastrup, Karla Frydenvang, Lennart Bunch

18 Citations (Scopus)

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 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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	15
Pages (from-to)	6131-50
Number of pages	20
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00750
Publication status	Published - 22 Jul 2015

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Krogsgaard-Larsen, N., Storgaard, M., Møller, C., Demmer, C. S., Hansen, J., Han, L., Monrad, R. N., Nielsen, B., Tapken, D., Pickering, D. S., Kastrup, J. S., 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, 58(15), 6131-50. https://doi.org/10.1021/acs.jmedchem.5b00750

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 et al.

In: Journal of Medicinal Chemistry, Vol. 58, No. 15, 22.07.2015, p. 6131-50.

Research output: Contribution to journal › Journal article › Research › peer-review

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

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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",

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doi = "10.1021/acs.jmedchem.5b00750",

language = "English",

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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 - 2015/7/22

Y1 - 2015/7/22

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

SN - 0022-2623

VL - 58

SP - 6131

EP - 6150

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -

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

Abstract

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