Aryl and cycloalkyl analogues of AMPA: synthetic, pharmacological and stereochemical aspects

Abstract

We have previously shown that ( RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA, 2) is a functional partial agonist at the ( RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) subtype of excitatory amino acid receptors, reflecting that ( S)-APPA is a full agonist and ( R)-APPA a competitive antagonist at AMPA receptors. We have now synthesized and pharmacologically characterized ( RS)-2-amino-3-[3-hydroxy-5-(2-fluorophenyl)isoxazol-4-yl]propionic acid (2-F-APPA, 5a), 3-F-APPA ( 5b), 4-F-APPA ( 5c), ( S)-4-F-APPA ( 6), ( R)-4-F-APPA ( 7), and the fully and partially, respectively, saturated APPA ( 2) analogues, ( RS)-2-amino-3-(hydroxy-5-cyclohexylisoxazol-4-yl)propionic acid ( 5d) and compound 5e containing a 1-cyclohexenyl ring. The absolute stereo-chemistry of 6 and 7 was established on the basis of comparative circular dichroism studies on 6, 7, and ( S)- and ( R)-APPA. 4-F-APPA ( 5c), ( S-4-F-APPA ( 6), 5d, and 5e were shown to selectively inhibit [ 3H]AMPA binding and to activate AMPA receptors. Whereas ( S)-4-F-APPA ( 6) showed full AMPA receptor agonism, ( R)-4-F-APPA ( 7) was an AMPA receptor antagonist. Co-administration of ( S)- and ( R)-4-F-APPA to the rat cortical wedge preparation produced functional partial AMPA receptor agonism. Semi empirical calculations showed that the magnitude of the torsional angle of the bond connecting the two rings in the series of nonannulated bicyclic AMPA analogues appears to be of importance for the potency and efficacy of these compounds.