Excitatory amino acid receptor ligands. Synthesis and biological activity of 3-isoxazolol amino acids structurally related to homoibotenic acid.
The 3-isoxazolol amino acid (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 2) and the isomeric compound (RS)-2-amino-3-(3-hydroxy-4-methylisoxazol-5-yl)propionic acid (4-methylhomoibotenic acid, 4a) are potent agonists at the AMPA subtype of central excitatory amino acid receptors. Using 4a as a lead structure, the amino acids 4c-e, in which the 4-methyl group of 4a is replaced by substituents of different size and polarity, were synthesized. Attempts to synthesize 4-(bromomethyl)homoibotenic acid (4f), a potential receptor alkylating agent, were unsuccessful. 4-Butylhomoibotenic acid (4c) and 4-(2-hydroxyethyl)homoibotenic acid (4e) were equipotent as inhibitors of [3H]AMPA binding (IC50 = 2 microM) and showed similar excitatory activity in the rat cortical slice preparation. 4d did not show significant affinity for AMPA receptor sites, but turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist. However, like 4c,e, 4d did not significantly affect the binding of the competitive NMDA antagonist, [3H]CPP, or the noncompetitive NMDA antagonist, [3H]MK-801. None of the amino acids 4c-e showed detectable affinity for [3H]kainic acid binding sites. Like the parent compound 4a (IC50 = 0.18 microM), 4c (IC50 = 0.18 microM), 4e (IC50 = 0.14 microM), and in particular 4d (IC50 = 0.02 microM) were effective inhibitors of calcium chloride-dependent [3H]glutamic acid binding, whereas AMPA is inactive (IC50 greater than 100 microM) in this binding assay. Thus, 4d is an effective and highly selective inhibitor of calcium chloride-dependent [3H]glutamic acid binding and may be a useful tool for studies of the physiological relevance and pharmacological importance of this binding affinity.
Christensen
I T
IT
Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
Ebert
B
B
Madsen
U
U
Nielsen
B
B
Brehm
L
L
Krogsgaard-Larsen
P
P
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017459:Receptors, Amino Acid / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D007555:Isoxazoles; D017459:Receptors, Amino Acid; D007051:Ibotenic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid