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

Abstract 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 (EC 50 2.3 μM) and lower affinity (IC 50 0.08 μM) for AMPA receptors than AMPA itself (EC 50 3.5 μM and IC 50 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 [ 3 H]kainic acid ([ 3 H]KAIN) binding (IC 50 7.1 μM) than AMPA (IC 50 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.