Synthesis and Pharmacology of Highly Selective Carboxy and Phosphono Isoxazole Amino Acid AMPA Receptor Antagonists
- 1 January 1996
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 39 (8), 1682-1691
- https://doi.org/10.1021/jm950826p
Abstract
(RS)-2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 5) and the selective AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA, 7) have been used as leads for the design and synthesis of a number of potential AMPA receptor antagonists. Two parallel series of AMOA analogs were synthesized, containing either a distal carboxylic acid (compounds 8b−g and 11b) or a phosphonic acid (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 substituent, (RS)-2-amino-3-[5-tert-butyl-3-(carboxymethoxy)-4-isoxazolyl]propionic acid (ATOA, 8b) and the corresponding phosphonic acid analog ATPO (9b), were the most potent and selective AMPA antagonists within each series. ATOA and ATPO showed IC50 values of 150 and 28 μM, respectively, toward AMPA-induced depolarizations in the cortical slice model compared to IC50 = 320 μM for the parent compound, AMOA. These two new competitive AMPA 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. The structure−activity relationships for the two series of compounds revealed considerable differences with respect to the substituents effects, and the phosphonic acid analogs generally exhibited significantly higher potencies compared to the carboxylic acid analogs.Keywords
This publication has 19 references indexed in Scilit:
- Age ConsiderationsNeurology, 1994
- Design, synthesis and pharmacology of model compounds for indirect elucidation of the topography of AMPA receptor sitesEuropean Journal of Medicinal Chemistry, 1993
- Excitatory amino acid receptor atagonists: synthesis and pharmacology of 3-(carboxymethoxy)isoxazoles derived from AMPABioorganic & Medicinal Chemistry Letters, 1993
- Novel class of amino acid antagonists at non-N-methyl-D-aspartic acid excitatory amino acid receptors. Synthesis, in vitro and in vivo pharmacology, and neuroprotectionJournal of Medicinal Chemistry, 1991
- Novel Glutamate Receptor Antagonists Selectively Protect Against Kainic Acid Neurotoxicity in Cultured Cerebral Cortex NeuronsJournal of Neurochemistry, 1990
- Treatment of Alzheimer's DiseaseThe British Journal of Psychiatry, 1990
- Structure-activity relationships in the development of excitatory ammo acid receptor agonists and competitive antagonistsTrends in Pharmacological Sciences, 1990
- Resolution of 5,6-Dihydroxy-2-(N,N-di -n-propylamino)tetralin in Relation to the Structural and Stereochemical Requirements for Centrally Acting Dopamine AgonistsJournal of Medicinal Chemistry, 1985
- Ibotenic Acid Analogues. Synthesis, Molecular Flexibility, and in Vitro Activity of Agonists and Antagonists at Central Glutamic Acid ReceptorsJournal of Medicinal Chemistry, 1985
- New class of glutamate agonist structurally related to ibotenic acidNature, 1980