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Pure Appl. Chem., 2004, Vol. 76, No. 5, pp. 921-930

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 Povl Krogsgaard-Larsen

Department of Medicinal Chemistry, The Danish University of Pharmaceutical 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 compounds 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.