Stereostructure-activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors
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Stereostructure-activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors. / Johansen, Tommy N; Greenwood, Jeremy R; Frydenvang, Karla Andrea; Madsen, Ulf; Krogsgaard-Larsen, Povl.
In: Chirality, Vol. 15, No. 2, 2003, p. 167-79.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Stereostructure-activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors
AU - Johansen, Tommy N
AU - Greenwood, Jeremy R
AU - Frydenvang, Karla Andrea
AU - Madsen, Ulf
AU - Krogsgaard-Larsen, Povl
N1 - Copyright 2003 Wiley-Liss, Inc.
PY - 2003
Y1 - 2003
N2 - (S)-Glutamic acid (Glu), the major excitatory neurotransmitter in the central nervous system, operates through ionotropic as well as metabotropic receptors and is considered to be involved in certain neurological disorders and degenerative brain diseases that are currently without any satisfactory therapeutic treatment. Until recently, development of selective Glu receptor agonists had mainly been based on lead compounds, which were frequently naturally occurring excitants structurally related to Glu. These Glu receptor agonists generally contain heterocyclic acidic moieties, which has stimulated the use of bioisosteric replacement approaches for the design of subtype-selective agonists. Furthermore, most of these leads are conformationally restricted and stereochemically well-defined Glu analogs. Crystallization of the agonist binding domain of the GluR2 subunit of the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of ionotropic Glu receptors in the presence or absence of an agonist has provided important information about ligand-receptor interaction mechanisms. The availability of these binding domain crystal structures has formed the basis for rational design of ligands, especially for the AMPA and kainate subtypes of ionotropic Glu receptors. This mini-review will focus on structure-activity relationships on AMPA and kainate receptor agonists with special emphasis on stereochemical and three-dimensional aspects.
AB - (S)-Glutamic acid (Glu), the major excitatory neurotransmitter in the central nervous system, operates through ionotropic as well as metabotropic receptors and is considered to be involved in certain neurological disorders and degenerative brain diseases that are currently without any satisfactory therapeutic treatment. Until recently, development of selective Glu receptor agonists had mainly been based on lead compounds, which were frequently naturally occurring excitants structurally related to Glu. These Glu receptor agonists generally contain heterocyclic acidic moieties, which has stimulated the use of bioisosteric replacement approaches for the design of subtype-selective agonists. Furthermore, most of these leads are conformationally restricted and stereochemically well-defined Glu analogs. Crystallization of the agonist binding domain of the GluR2 subunit of the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of ionotropic Glu receptors in the presence or absence of an agonist has provided important information about ligand-receptor interaction mechanisms. The availability of these binding domain crystal structures has formed the basis for rational design of ligands, especially for the AMPA and kainate subtypes of ionotropic Glu receptors. This mini-review will focus on structure-activity relationships on AMPA and kainate receptor agonists with special emphasis on stereochemical and three-dimensional aspects.
KW - Animals
KW - Crystallography, X-Ray
KW - Humans
KW - Kainic Acid
KW - Ligands
KW - Models, Molecular
KW - Molecular Conformation
KW - Molecular Structure
KW - Receptors, AMPA
KW - Receptors, Glutamate
KW - Receptors, Kainic Acid
KW - Stereoisomerism
KW - Structure-Activity Relationship
U2 - 10.1002/chir.10177
DO - 10.1002/chir.10177
M3 - Journal article
C2 - 12520509
VL - 15
SP - 167
EP - 179
JO - Chirality
JF - Chirality
SN - 0899-0042
IS - 2
ER -
ID: 40371630