EXCITATORY AMINO-ACID RECEPTOR AGONISTS - SYNTHESIS AND PHARMACOLOGY OF ANALOGS OF AMINO-3-(3-HYDROXY-5-METHYLISOXAZOL-4-YL)PROPIONIC ACID

We have previously proposed the existence of a lipophilic cavity of th e -amino-3-(3-hydroxy-5-methylisoxazol4-yl)propionic acid (AMPA) recep tor recognition site capable of accommodating alkyl substituents of li mited size in the 5-position of the isoxazole ring. In order to indire ctly elucidate the approximate extent of this proposed cavity we have synthesized and pharmacologically characterized a number of AMPA analo gues. For most of these AMPA analogues, a positive correlation between AMPA receptor affinity and agonist effect was observed. The only exce ption was demethyl-AMPA (8a), which showed relatively high AMPA recept or affinity (IC50 = 0.27 mu M) but remarkably weak agonist potency (EC 50 = 900 mu M). Whereas the ethyl analogue of AMPA (Et-AMPA) (IC50 = 0 .030 mu M; EC50 = 2.3 mu M) has previously been shown to be slightly m ore potent than AMPA (IC50 = 0.040 mu M; EC50 = 3.5 mu M), substitutio ns of a propyl or a butyl group for the methyl group of AMPA to give 8 b (IC50 = 0.090 mu M; EC50 = 5.0 mu M) or 8f (IC50 = 1.0 mu M; EC50 = 32 mu M), 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, wer e very weak or totally inactive as AMPA receptor ligands.