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 neuroprotection.

Article date: 1991/1/1

PubMed ID: 1825114

Journal name: Journal of medicinal chemistry (ISSN: 0022-2623)


The isoxazole amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) (1), which is a highly selective agonist at the AMPA subtype of excitatory amino acid (EAA) receptors, has been used as a lead for the development of two novel EAA receptor antagonists. One of the compounds, 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionic acid (AMOA, 7), was synthesized via O-alkylation by ethyl chloroacetate of the amino acid protected AMPA derivative 4. The other compound, 2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-+ ++oxoisoxazolin -4-yl]propionic acid (AMNH, 14) was synthesized with use of 4-(chloromethyl)-3-methoxy-5-methylisoxazole (8) as the starting material. The intermediate 4-(chloromethyl)-2-(3-methoxy-5-methylisoxazol-4-yl)methyl-5-me thylisoxazolin- 3-one (11) was converted into the acetamidomalonate (12), which was stepwise deprotected to give 14. Compounds 7 and 14 were stable in aqueous solution at pH values close to physiological pH. Neither 7 nor 14 showed detectable affinities for the receptor, ion channel, or modulatory sites of the N-methyl-D-aspartic acid (NMDA) receptor complex. Quantitative receptor autoradiographic and conventional binding techniques were used to study the affinities of 7 and 14 for non-NMDA receptor sites. Both compounds were inhibitors of the binding of [3H]AMPA (IC50 = 90 and 29 microM, respectively). Compounds 14 and 7 were both very weak inhibitors of the high-affinity binding of radioactive kainic acid [( 3H]KAIN). Compound 14, but not 7, was, however, shown to be an inhibitor of low-affinity [3H]KAIN binding (IC50 = 40 microM) as determined in the presence of 100 mM calcium chloride. In the rat cortical slice preparation, 7 was shown to antagonize excitation induced by 1 with some selectivity, whereas 14 proved to be a rather selective antagonist of KAIN-induced excitation. Both antagonists showed very weak effects on the excitatory effects of NMDA. Compound 7 was a poor antagonist of excitation by quisqualic acid (2), whereas 14 did not affect excitation by this nonselective AMPA receptor agonist. On cat spinal neurones, both 7 and 14 reduced excitations by 1 and KAIN, but, again, the excitatory effects of 2 were much less sensitive. Compound 14 and, in particular, 7 effectively protected rat striatal neurones against the neurotoxic effects of KAIN, whereas the toxic effects of 1 were reduced only by 7. Neither antagonist showed protection against the cell damage caused by intrastriatal injection of the NMDA agonist quinolinic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

This document is available from: http://directlinks.cc/files/muscimol/1825114.pdf

Author List: Krogsgaard-Larsen P, Ferkany J W, Nielsen E O, Madsen U, Ebert B, Johansen J S, Diemer N H, Bruhn T, Beattie D T, Curtis D R

Publication Types: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't

Substances mentioned in the article: Indicators and Reagents; Isoxazoles; Propionates; Receptors, N-Methyl-D-Aspartate; Tritium; 2-amino-3-(3-(carboxymethoxy)-5-methylisoxazol-4-yl)propionic acid; 2-amino-3-(2-(3-hydroxy-5-methylisoxazol-4-yl)methyl-5-methyl-3-oxoisoxazolin-4-yl)propionic acid; Ibotenic Acid; Dizocilpine Maleate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Glycine;

Mesh terms: Animals; Autoradiography; Binding, Competitive; Brain/metabolism; Cerebral Cortex/drug effects; Dizocilpine Maleate/metabolism; Glycine/metabolism; Ibotenic Acid/analogs & derivatives; In Vitro Techniques; Indicators and Reagents; Isoxazoles/chemical synthesis; Male; Molecular Structure; Neurons/drug effects; Propionates/chemical synthesis; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate/drug effects; Structure-Activity Relationship; Tritium; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;

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