Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Ann Møller Larsen; Raminta Venskutonyte; Elena Antón Valadés; Birgitte Nielsen; Darryl S Pickering; Lennart Bunch

doi:10.1021/cn100093f

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Ann Møller Larsen, Raminta Venskutonyte, Elena Antón Valadés, Birgitte Nielsen, Darryl S Pickering, Lennart Bunch

14 Citationer (Scopus)

Abstract

The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/
or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we
present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 µM; KA, 22 µM; NMDA 6 µM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 µM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a Kb of 11.4 µM.

Originalsprog	Engelsk
Tidsskrift	ACS Chemical Neuroscience
Vol/bind	2
Udgave nummer	2
Sider (fra-til)	107-114
Antal sider	8
ISSN	1948-7193
DOI	https://doi.org/10.1021/cn100093f
Status	Udgivet - 16 feb. 2011

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10.1021/cn100093f

http://pubs.acs.org/doi/full/10.1021/cn100093f

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Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid. / Larsen, Ann Møller; Venskutonyte, Raminta; Valadés, Elena Antón et al.

I: ACS Chemical Neuroscience, Bind 2, Nr. 2, 16.02.2011, s. 107-114.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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title = "Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid",

abstract = "The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 µM; KA, 22 µM; NMDA 6 µM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 µM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a Kb of 11.4 µM.",

author = "Larsen, {Ann M{\o}ller} and Raminta Venskutonyte and Valad{\'e}s, {Elena Ant{\'o}n} and Birgitte Nielsen and Pickering, {Darryl S} and Lennart Bunch",

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AU - Larsen, Ann Møller

AU - Venskutonyte, Raminta

AU - Valadés, Elena Antón

AU - Nielsen, Birgitte

AU - Pickering, Darryl S

AU - Bunch, Lennart

PY - 2011/2/16

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N2 - The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 µM; KA, 22 µM; NMDA 6 µM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 µM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a Kb of 11.4 µM.

AB - The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 µM; KA, 22 µM; NMDA 6 µM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 µM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a Kb of 11.4 µM.

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DO - 10.1021/cn100093f

M3 - Journal article

C2 - 22778860

SN - 1948-7193

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ER -

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Abstract

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