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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	58
Udgave nummer	15
Sider (fra-til)	6131-50
Antal sider	20
ISSN	0022-2623
DOI	https://doi.org/10.1021/acs.jmedchem.5b00750
Status	Udgivet - 22 jul. 2015

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10.1021/acs.jmedchem.5b00750

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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.

I: Journal of Medicinal Chemistry, Bind 58, Nr. 15, 22.07.2015, s. 6131-50.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 58, nr. 15, s. 6131-50. https://doi.org/10.1021/acs.jmedchem.5b00750

@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",

month = jul,

day = "22",

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",

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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 - 2015/7/22

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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