DESIGN, SYNTHESIS AND PHARMACOLOGY OF MODEL COMPOUNDS FOR INDIRECT ELUCIDATION OF THE TOPOGRAPHY OF AMPA RECEPTOR-SITES

Based on structure-activity studies on excitatory amino acids with spe cific agonist effect at amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propi onic acid (AMPA) receptors we have earlier proposed a simple model of the AMPA receptor pharamacophore. In order to judge the capacity of th is empirical model we have now synthesized and tested 3 model compound s derived from the AMPA receptor agonists, AMPA and ,7-tetrahydroisoxa zolo[5,4-c]pyridine-7-carboxylic acid (7-HCPA). These model compounds, -amino-3-(5-ethyl-3-hydroxy-4-isoxazolyl)propionic acid (Et-AMPA), 2- amino-4-(3-hydroxy-5-methyl-4-isoxazolyl)butyric acid (Homo-AMPA) and tetrahydro-4H-isoxazolo[5,4-c]azepine-8-carboxylic acid (Homo-7-HCPA) were tested electrophysiologically and in receptor binding assays. Et- AMPA was slightly more potent than AMPA as an AMPA agonist (EC50 = 2.3 muM compared to 3.5 muM for AMPA) and as a specific inhibitor of [H-3 ]AMPA binding (IC50 = 0.030 muM compared with 0.040 muM for AMPA), whe reas Homo-AMPA was essentially inactive. Homo-7-HPCA was much weaker t han 7-HPCA. These data support the view that the AMPA recognition site (s) comprise a confined region, which tightly binds the charged struct ure-elements of agonists molecules, and a cavity capable of accommodat ing bulky lipophilic groups in such compounds.