Excitatory amino-acid receptor agonists. Synthesis and pharmacology of analogues of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid.

Article abstract of DOI:10.1016/S0223-5234(97)89085-X

We have previously proposed the existence of a lipophilic cavity of the 2-amino-3-(3 -hydroxy-5 -methylisoxazol-4-yl)propionic acid (AMPA) receptor recognition site capable of accommodating alkyl substituents of limited size in the 5-position of the isoxazole ring. In order to indirectly elucidate the approximate extent of this proposed cavity we have synthesized and pharmacologically characterized a number of AMPA analogues. For most of these AMPA analogues, a positive correlation between AMPA receptor affinity and agonist effect was observed. The only exception was demethyl-AMPA (8a), which showed relatively high AMPA receptor affinity (IC₅₀, = 0.27 μM) but remarkably weak agonist potency (EC₅₀ = 900 μM). Whereas the ethyl analogue of AMPA (Et-AMPA) (IC₅₀ = 0.030 μM; EC₅₀ = 2.3 μM) has previously been shown to be slightly more potent than AMPA (IC₅₀ = 0.040 μM; EC₅₀ = 3.5 μM), substitutions of a propyl or a butyl group for the methyl group of AMPA to give 8b IC₅₀ = 0.090 μM; EC₅₀ = 5.0 μM) or 8f (IC₅₀ = 1.0 μM; EC₅₀ = 32 μM), respectively, result in progressive loss of the AMPA agonist effect. Analogues containing larger groups, such as isopentyl (8e), 1-propylbutyl (8g), 2,2-dimethylpropyl (8h), or benzyl (14) groups, were very weak or totally inactive as AMPA receptor ligands.