Design, synthesis and pharmacology of model compounds for indirect elucidation of the topography of AMPA receptor sites

Article abstract of DOI:10.1016/0223-5234(93)90114-T

Based on structure-activity studies on excitatory amino acids with specific agonist effect at (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors we have earlier proposed a simple model of the AMPA receptor pharmacophore. In order to judge the capacity of this empirical model we hvae now synthesized and tested 3 model compounds derived from the AMPA receptor agonists, AMPA and (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7- carboxylic acid (7-HPCA). These model compounds, (RS)-2-amino-3-(5-ethyl-3-hydroxy-4-isoxazolyl)propionic acid (Et-AMPA), (RS)-2-amino-4-(3-hydroxy-5-methyl-4-isoxazolyl)butyric acid (Homo-AMPA) and (RS)-3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo[5,4-c]azepine-8- carboxylic acid (Homo-7-HPCA) were tested electrophysiologically and in receptor binding assays. Et-AMPA was slightly more potent than AMPA as an AMPA agonist (EC₅₀ = 2.3 μM compared to 3.5 μM for AMPA) and as a specific inhibitor of [³H]AMPA binding (IC₅₀ = 0.030 μM compared with 0.040 μM for AMPA), whereas Homo-AMPA was essentially inactive. Homo-7-HPCA was much weaker than 7-HPCA. These data support the view that the AMPA recognition site(s) comprise a confined region, which tightly binds the charged structure-elements of agonists molecules, and a cavity capable of accommodating bulky lipophilic groups in such compounds.