Structural and pharmacological characterization of phenylalanine-based AMPA receptor antagonists at kainate receptors

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

SN - 1860-7179

VL - 7

SP - 1793

EP - 1798

JO - ChemMedChem

JF - ChemMedChem

IS - 10

ER -