Structure−Activity Studies for α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid Receptors: Acidic Hydroxyphenylalanines

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Abstract
Antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptors may have therapeutic potential as psychotropic agents. A series of mononitro- and dinitro-2- and 3-hydroxyphenylalanines was prepared, and their activity compared with willardiine, 5-nitrowillardiine, AMPA, and 2,4,5-trihydroxyphenylalanine (6-hydroxydopa) as inhibitors of specific [3H]AMPA and [3H]kainate binding in rat brain homogenates. The most active compounds were highly acidic (pKa 3−4), namely, 2-hydroxy-3,5-dinitro-dl-phenylalanine (13; [3H]AMPA IC50 ≈ 25 μM) and 3-hydroxy-2,4-dinitro-dl-phenylalanine (19; [3H]AMPA IC50 ≈ 5 μM). Two other dinitro-3-hydroxyphenylalanines, and 3,5-dinitro-dl-tyrosine, were considerably less active. Various mononitrohydroxyphenylalanines, which are less acidic, were also less active or inactive, and 2- and 3-hydroxyphenylalanine (o- and m-tyrosine) were inactive. Compounds 13 and 19, dl-willardiine (pKa 9.3, [3H]AMPA IC50 = 2 μM), and 5-nitro-dl-willardiine (pKa 6.4, [3H]AMPA IC50 = 0.2 μM) displayed AMPA ≫ kainate selectivity in binding studies. Compound 19 was an AMPA-like agonist, but 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 systemic amphetamine.

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