Structural and pharmacological characterization of phenylalanine-based AMPA receptor antagonists at kainate receptors
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Structural and pharmacological characterization of phenylalanine-based AMPA receptor antagonists at kainate receptors. / Venskutonyte, Raminta; Frydenvang, Karla; Valadés, Elena Antón; Szymanska, Ewa Monika; Johansen, Tommy N; Kastrup, Jette S; Pickering, Darryl S.
In: ChemMedChem, Vol. 7, No. 10, 10.2012, p. 1793-1798.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural and pharmacological characterization of phenylalanine-based AMPA receptor antagonists at kainate receptors
AU - Venskutonyte, Raminta
AU - Frydenvang, Karla
AU - Valadés, Elena Antón
AU - Szymanska, Ewa Monika
AU - Johansen, Tommy N
AU - Kastrup, Jette S
AU - Pickering, Darryl S
N1 - Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2012/10
Y1 - 2012/10
N2 - Continued efforts into the discovery of ligands that target ionotropic glutamate receptors (iGluRs) are important for studies of the physiological roles of the various iGluR subtypes as well as for the search for drugs that can be used in the treatment of diseases of the central nervous system. A new series of phenylalanine derivatives that target iGluRs was reported to bind AMPA receptors. Herein we report our studies of these compounds at the kainate receptors GluK1-3. Several compounds bind with micromolar affinity at GluK1 and GluK3, but do not bind GluK2. The crystal structure of the most potent compound in the ligand binding domain of GluK1 revealed different modes of binding to GluK1 and GluA2, due primarily to residues Ser741 (GluK1) and Met729 (GluA2). The compound was shown to be slightly more potent at GluK1 than at AMPA receptors and to induce a domain closure similar to that observed in GluK1 structures with partial agonists.
AB - Continued efforts into the discovery of ligands that target ionotropic glutamate receptors (iGluRs) are important for studies of the physiological roles of the various iGluR subtypes as well as for the search for drugs that can be used in the treatment of diseases of the central nervous system. A new series of phenylalanine derivatives that target iGluRs was reported to bind AMPA receptors. Herein we report our studies of these compounds at the kainate receptors GluK1-3. Several compounds bind with micromolar affinity at GluK1 and GluK3, but do not bind GluK2. The crystal structure of the most potent compound in the ligand binding domain of GluK1 revealed different modes of binding to GluK1 and GluA2, due primarily to residues Ser741 (GluK1) and Met729 (GluA2). The compound was shown to be slightly more potent at GluK1 than at AMPA receptors and to induce a domain closure similar to that observed in GluK1 structures with partial agonists.
U2 - 10.1002/cmdc.201100599
DO - 10.1002/cmdc.201100599
M3 - Journal article
C2 - 22407805
VL - 7
SP - 1793
EP - 1798
JO - Farmaco
JF - Farmaco
SN - 1860-7179
IS - 10
ER -
ID: 38166798