Stereostructure-activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors

(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.