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

TY - JOUR

T1 - Ionotropic excitatory amino acid receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antagonist

AU - Madsen, U

AU - Sløk, F A

AU - Stensbøl, T B

AU - Bräuner-Osborne, Hans

AU - Lützhøft, H H

AU - Poulsen, M V

AU - Eriksen, L

AU - Krogsgaard-Larsen, P

PY - 2000/1

Y1 - 2000/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cerebral Cortex

KW - Electrophysiology

KW - Excitatory Amino Acid Antagonists

KW - Isoxazoles

KW - N-Methylaspartate

KW - Propionates

KW - Quinoxalines

KW - Rats

KW - Receptors, AMPA

KW - Receptors, Glutamate

KW - Receptors, N-Methyl-D-Aspartate

KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

M3 - Journal article

C2 - 10733604

SN - 0223-5234

VL - 35

SP - 69

EP - 76

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

IS - 1

ER -