Synthesis and pharmacology of (RS)-2-amino-3-(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid, a potent AMPA receptor agonist

Article abstract of DOI:10.1016/0223-5234(92)90181-Y

Three isoxazole bioisosteres of glutamic acid derived from the specific AMPA receptor agonist (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) were synthesized and tested electrophysiologically and in different receptor binding systems. (RS)-2-Amino-3-(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid (trifluoro-AMPA, 8) showed more potent agonist activity (EC₅₀ 2.3 μM) and lower affinity (IC₅₀ 0.08 μM) for AMPA receptors than AMPA itself (EC₅₀ 3.5 μM and IC₅₀ 0.04 μM, respectively). Like AMPA, trifluoro-AMPA (8) did not bind significantly to N-methyl-D-aspartic acid (NMDA) receptor sites, but trifluoro-AMPA (8) was more potent as an inhibitor of [³H]kainic acid ([³H]KAIN) binding (IC₅₀ 7.1 μM) than AMPA (IC₅₀ 32 μM). (RS)-2-Amino-3-(3-chloro-5-methyl-4-isoxazolyl)propionic acid (14), the 3-chloro analogue of AMPA, and the isomeric compound (RS)-2-amino-3-(3-chloro-4-methyl-5-isoxazolyl)propionic acid (15), did not show significant neuroexcitatory effects at or affinities for AMPA, NMDA, or KAIN receptor sites.