SYNTHESIS AND PHARMACOLOGY OF HIGHLY SELECTIVE CARBOXY AND PHOSPHONO ISOXAZOLE AMINO-ACID AMPA RECEPTOR ANTAGONISTS

Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 5) and the selective AMPA receptor antagonist 3-(carboxymethoxy)-5-methyl-4-i soxazolyl]propionic acid (AMOA, 7) have been used as leads for the des ign and synthesis of a number of potential AMPA receptor antagonists. Two parallel series of AMOA analogs were synthesized, containing eithe r a distal carboxylic acid (compounds 8b-g and 11b) or a phosphonic ac id (compounds 9a-g, 10c, and 11c). Pharmacological characterization of the synthesized compounds was carried out using a series of receptor binding assays and by in vitro electrophysiological experiments using the rat cortical slice model. The two analogs with a tert-butyl substi tuent, rt-butyl-3-(carboxymethoxy)-4-isoxazolyl]propionic acid (ATOA, 8b) and the corresponding phosphonic acid analog ATPO (9b), were the m ost potent and selective AMPA antagonists within each series. ATOA and ATPO showed IC50 values of 150 and 28 mu M, respectively, toward AMPA -induced depolarizations in the cortical slice model compared to IC50 = 320 mu M for the parent compound, AMOA. These two new competitive AM PA antagonists were significantly more selective than AMOA, showing no antagonism (up to 1 mM) toward NMDA-induced responses, whereas AMOA ( at 1 mM) showed weak (19%) inhibition toward NMDA-induced responses. T he structure-activity relationships for the two series of compounds re vealed considerable differences with respect to the substituents effec ts, and the phosphonic acid analogs generally exhibited significantly higher potencies compared to the carboxylic acid analogs.