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

摘要: (S)-Glutamic acid (Glu), the major excitatory neurotransmitter in central nervous system, operates through ionotropic as well metabotropic receptors and is considered to be involved certain neurological disorders 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 Glu. These generally contain heterocyclic acidic moieties, has stimulated use bioisosteric replacement approaches for design subtype-selective agonists. Furthermore, most these leads conformationally restricted stereochemically well-defined analogs. Crystallization agonist binding domain GluR2 subunit (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic (AMPA) subtype presence or absence an provided important information about ligand–receptor interaction mechanisms. The availability crystal structures formed basis rational ligands, especially AMPA kainate subtypes receptors. This mini-review will focus structure–activity relationships with special emphasis stereochemical three-dimensional aspects. Chirality 15:167–179, 2003. © 2003 Wiley-Liss, Inc.