Excitatory amino acid agonists and partial agonists

The racemic 3-isoxazolol amino acids α-amino-3-hydroxy-5-methyl-4-isoxazolepentanoic acid [(2)homo-AMPA] (12) and α-amino-3-hydroxy-5-phenyl-4-isoxazolepropanoic acid (APPA) (19) were synthesized and tested biologically. The two compounds are structurally related to AMPA, whihc is a potent and highly selective agonist at the QUIS/AMPA subtype of central excitatory amino acid (EAA) receptors. Both were shown to be neuronal excitants, though less potent than the parent compound. The full EAA agonistic effect of (2)homo-AMPA (12) could be blocked by the non-NMDA antagonist CNQX but was insensitive to AP5, an antagonist at the NMDA subtype of EAA receptors. It was an inhibitor of the binding of [³H]AMPA (IC₅₀ 49 μM) and of the calcium chloride-dependent binding of [³H]glutamic acid (IC₅₀ 3 μM), but did not show significant affinity for kainic acid binding sites or glutamic acid uptake mechanisms. APPA (19) proved to be a relatively selective partial agonist at QUIS/AMPA receptors. Thus, CNQX reduced the excitatory effect of 19 by more than 70%, whereas this effect of 19 was reduced by less than 10% in the presence of AP5. Like (2)homo-AMPA (12), 19 was an inhibitor of [³H]AMPA binding (IC₅₀ 50 μM) and did not inhibit [³H]kainic acid binding or glutamic acid uptake. However, in contrast to 12, 19 did not affect the calcium chloride-dependent binding of [³H]glutamic acid.