Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid
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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; Nielsen, Birgitte; Pickering, Darryl S; Bunch, Lennart.
In: ACS Chemical Neuroscience, Vol. 2, No. 2, 04.11.2011, p. 107-114.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid
AU - Larsen, Ann Møller
AU - Venskutonyte, Raminta
AU - Valadés, Elena Antón
AU - Nielsen, Birgitte
AU - Pickering, Darryl S
AU - Bunch, Lennart
PY - 2011/11/4
Y1 - 2011/11/4
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.
U2 - 10.1021/cn100093f
DO - 10.1021/cn100093f
M3 - Journal article
C2 - 22778860
VL - 2
SP - 107
EP - 114
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 2
ER -
ID: 32639600