Heterocyclic excitatory amino acids. Synthesis and biological activity of novel analogues of AMPA.

Article date: 1992/1/1

PubMed ID: 1370693

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


The novel acidic amino acids 6a-c, 7, and 8 have been synthesized via 1,3-dipolar cycloadditions, using nitrile oxides and alkynes. The prepared compounds are heterocyclic analogues of glutamic acid with differing chain lengths. One of these compounds, (RS)-2-amino-3-(3-carboxy-5-methyl-4- isoxazolyl)propionic acid (ACPA, 8), was shown in [3H]AMPA binding studies to be more active than AMPA itself (IC50 = 20 nM compared to IC50 = 79 nM for AMPA). No affinity for NMDA receptors (NMDA-sensitive [3H]glutamic acid binding) was found, and only weak affinity in [3H]kainic acid binding (IC50 = 6.3 microM) was detected. The excitatory activity in rat cortical wedge also showed that ACPA was more potent than AMPA (EC50 = 1.0 microM compared to EC50 = 3.5 microM for AMPA). The depolarizing effect of ACPA could be fully antagonized by the selective non-NMDA antagonist 6-cyano-7-nitro-quinoxazoline-2,3-dione (CNQX), but was unaffected by the selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (AP5).

Author List: Madsen U, Wong E H

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

Substances mentioned in the article: Amino Acids; Heterocyclic Compounds; Receptors, Amino Acid; Receptors, Cell Surface; Ibotenic Acid; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;

Mesh terms: Amino Acids/chemical synthesis; Animals; Brain/metabolism; Electrophysiology; Heterocyclic Compounds/chemical synthesis; Ibotenic Acid/analogs & derivatives; Rats; Receptors, Amino Acid; Receptors, Cell Surface/metabolism; Structure-Activity Relationship; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;

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