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

Journal Article · Tue Jan 01 04:00:00 EST 1991 · Journal of Medicinal Chemistry; (USA)

DOI:https://doi.org/10.1021/jm00105a019· OSTI ID:6057576

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 ^[1]

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1. Royal Danish School of Pharmacy, Copenhagen (Denmark)

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 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.

• OSTI ID: 6057576
• Journal Information: Journal of Medicinal Chemistry; (USA), Journal Name: Journal of Medicinal Chemistry; (USA) Vol. 34:1; ISSN JMCMA; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINO ACIDS
ANIMAL CELLS
ANIMALS
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL FUNCTIONS
BODY
BRAIN
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM
CHEMICAL PREPARATION
FUNCTIONS
GLYCINE
HYDROGEN COMPOUNDS
IN VITRO
IN VIVO
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MEMBRANE PROTEINS
MONOCARBOXYLIC ACIDS
NERVE CELLS
NERVOUS SYSTEM
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PROPIONIC ACID
PROTEINS
RATS
REACTION KINETICS
RECEPTORS
RODENTS
SOMATIC CELLS
STRUCTURE-ACTIVITY RELATIONSHIPS
SYNTHESIS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES