STRUCTURE-ACTIVITY STUDIES FOR LPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPANOIC ACID RECEPTORS - ACIDIC HYDROXYPHENYLALANINES

Antagonists of lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptors may have therapeutic potential as psychotropic agent s. A series of mononitro- and dinitro-2- and 3-hydroxyphenylalanines w as prepared, and their activity compared with willardiine, 5-nitrowili ardiine, AMPA, and 2,4,5-trihydroxyphenylalanine (6-hydroxydopa) as in hibitors of specific [H-3]AMPA and [H-3]kainate binding in rat brain h omogenates. The most active compounds were highly acidic (pK(a) 3-4), namely, 2-hydroxy-3,5-dinitro-DL-phenylalanine (13; [H-3]AMPA IC50 app roximate to 25 mu M) and 3-hydroxy-2,4-dinitro-DL-phenylalanine (19; [ H-3]AMPA IC50 approximate to 5 mu M). Two other dinitro-3-hydroxypheny lalanines, and 3,5-dinitro-DL-tyrosine, were considerably less active. Various mononitrohydroxyphenylalanines, which are less acidic, were a lso less active or inactive, and 2- and 3-hydroxyphenylalanine to-and m-tyrosine) were inactive. Compounds 13 and 19, DL-willardiine (pK(a) 9.3, [H-3]AMPA IC50 = 2 mu M), and 5-nitro-DL-willardiine (pK(a) 6.4, [H-3]AMPA IC50 = 0.2 mu M) displayed AMPA much greater than kainate se lectivity in binding studies. Compound 19 was an AMPA-like agonist, bu t 13 was an antagonist in an AMPA-evoked norepinephrine release assay in rat hippocampal nerve endings. Also, compound 13 injected into the rat ventral pallidum antagonized the locomotor activity elicited by sy stemic amphetamine.