Structural basis for 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor activation
T. N. Johansen, J. R. Greenwood, S. B. Vogensen, and P. Krogsgaard-Larsen
Department of Medicinal Chemistry, The Danish University
Sciences, Universitetsparken 2, DK-2100, Copenhagen, Denmark
Abstract: (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 a number of degenerative brain diseases that are currently
without any satisfactory therapeutic treatment. Until recently, development
of selective Glu receptor agonists had mainly been based on structural
optimization of naturally occurring lead com-
pounds structurally related to Glu. Crystallization of the agonist binding
domain of the GluR2 subunit of the 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic
acid (AMPA) receptor subtype of ionotropic Glu receptors (iGluRs) in
the presence or absence of an agonist has provided important information
about ligand-receptor interaction mechanisms. The availability of such
binding domain crystal structures has formed the basis for rational
design of ligands, especially for the AMPA subtypes of iGluRs.
*Lecture presented at the Polish-Austrian-German-Hungarian-Italian Joint Meeting on Medicinal Chemistry, Kraków, Poland, 15-18 October 2003. Other presentations are published in this issue, pp. 907 -1032.
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