Structure--activity studies for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid receptors: acidic hydroxyphenylalanines.
Antagonists of alpha-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 approximately equal to 25 microM) and 3-hydroxy-2,4-dinitro-DL-phenylalanine (19; [3H]AMPA IC50 approximately equal to 5 microM). 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 microM), and 5-nitro-DL-willardiine (pKa 6.4, [3H]AMPA IC50 = 0.2 microM) 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.
Hill
R A
RA
College of Pharmacy, Ohio State University, Columbus 43210-1291, USA.
Wallace
L J
LJ
Miller
D D
DD
Weinstein
D M
DM
Shams
G
G
Tai
H
H
Layer
R T
RT
Willins
D
D
Uretsky
N J
NJ
Danthi
S N
SN
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D007536:Isomerism; D008956:Models, Chemical; D016202:N-Methylaspartate / Q000378:metabolism; D010622:Phencyclidine / Q000378:metabolism; D011810:Quinoxalines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; C107610:3,5-dinitrotyrosine; D014443:Tyrosine; C056723:FG 9041; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C026741:2-tyrosine; C015566:3-tyrosine; D010622:Phencyclidine