+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Ionotropic excitatory amino acid receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antagonist



Ionotropic excitatory amino acid receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antagonist



European Journal of Medicinal Chemistry 35(1): 69-76



We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA). Using these AMPA receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA receptors. The synthesized compounds have been tested for activity at ionotropic excitatory amino acid (EAA) receptors using receptor binding and electrophysiological techniques, and for activity at metabotropic EAA receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2), on the other hand, was shown to be a selective AMPA receptor antagonist (IC(50) = 73 microM), more potent in electrophysiological experiments than AMOA (IC(50) = 320 microM). The isomeric analogue of 2, compound 5, did not show AMPA antagonist effects, but was a weak NMDA receptor antagonist (IC(50) = 540 microM). Finally, compound 3, which is an isomer of ACPA, turned out to be a very weak NMDA antagonist, and an AMPA receptor agonist approximately 1000 times weaker than ACPA. None of the compounds showed agonist or antagonist effects at metabotropic EAA receptors.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 010884612

Download citation: RISBibTeXText

PMID: 10733604

DOI: 10.1016/s0223-5234(00)00104-5


Related references

In vitro and in vivo pharmacology of trans- and cis-(+-)-1-amino-1,3-cyclopentanedicarboxylic acid: dissociation of metabotropic and ionotropic excitatory amino acid receptor effects. Journal of Neurochemistry 56(5): 1789-1796, 1991

Excitatory amino acid receptor ligands: asymmetric synthesis, absolute stereochemistry and pharmacology of (R)- and (S)-homoibotenic acid. Bioorganic and Medicinal Chemistry 3(5): 553-558, 1995

Excitatory amino acid receptor antagonists: Synthesis and pharmacology of 3-(carboxymethoxy)isoxazoles derived from AMPA. Bioorganic and Medicinal Chemistry Letters 3(8): 1649-1654, 1993

Excitatory amino acid receptor atagonists: synthesis and pharmacology of 3-(carboxymethoxy)isoxazoles derived from AMPA. Bioorganic and Medicinal Chemistry Letters 3(8): 1649-1654, 1993

Excitatory amino-acid receptor agonists: Synthesis and pharmacology of analogues of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid. European Journal of Medicinal Chemistry 32(4): 329-338, 1997

Metabotropic excitatory amino acid receptor agonists selectively potentiate behavioral effects induced by ionotropic excitatory amino acid receptor agonists in mice. European Journal of Pharmacology 250(1): 9-13, 1993

Dissociation of metabotropic and ionotropic excitatory amino acid receptor effects in vivo using trans and cis racemic amino 1 3 cyclopentanedicarboxylic acid. Society for Neuroscience Abstracts 16(1): 618, 1990

Design and Synthesis of 2,3- trans-Proline Analogues as Ligands for Ionotropic Glutamate Receptors and Excitatory Amino Acid Transporters. Acs Chemical Neuroscience 10(6): 2989-3007, 2019

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 of Medicinal Chemistry 34(1): 123-130, 1991

LY262466, DL-2-amino-3- -propanoic acid hydrochloride, a novel and selective agonist at the AMPA excitatory amino acid receptor. Society for Neuroscience Abstracts 19(1-3): 292, 1993

Synthesis and single cell pharmacology of potential heterocyclic bioisosteres of the excitatory amino acid antagonist glutamic acid diethyl ester. Acta Chemica Scandinavica 44(1): 96-102, 1990

Molecular pharmacology of 4-substituted glutamic acid analogues at ionotropic and metabotropic excitatory amino acid receptors. European Journal of Pharmacology 335(2-3): R1-R3, 1997

Effects of ionotropic excitatory amino acid receptor antagonists on glutamate transport and transport-mediated changes in extracelluar excitatory amino acids in the rat striatum. Journal of Neurochemistry 64(4): 1598-1604, 1995

Systemic excitatory amino acid receptor antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and of the N-methyl-D-aspartate (NMDA) receptor relieve mechanical hypersensitivity after transient spinal cord ischemia in rats. Journal of Pharmacology and Experimental Therapeutics 267(1): 140-144, 1993

Excitatory amino acid receptor ligands: resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid. Journal of Medicinal Chemistry 41(6): 930-939, 1998