Tetrazolyl isoxazole amino acids as ionotropic glutamate receptor antagonists: Synthesis, modelling and molecular pharmacology
Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b, of ( RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA receptor agonist, and ( RS)-2-amino-3-(5- tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring agonist, were synthesized. Compounds 1a...
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Published in | Bioorganic & medicinal chemistry Vol. 13; no. 18; pp. 5391 - 5398 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Elsevier Ltd
15.09.2005
Elsevier Science |
Subjects | |
Online Access | Get full text |
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Summary: | Two 3-(5-tetrazolylmethoxy) analogues,
1a and
1b, of (
RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA receptor agonist, and (
RS)-2-amino-3-(5-
tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring agonist, were synthesized. Compounds
1a and
1b were pharmacologically characterized in receptor binding assays, and electrophysiologically on homomeric AMPA receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid receptors, using two-electrode voltage-clamped
Xenopus laevis oocytes expressing these receptors. Both analogues proved to be antagonists at all AMPA receptor subtypes, showing potencies (
K
b
=
38–161
μM) similar to that of the AMPA receptor antagonist (
RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) (
K
b
=
43–76
μM). Furthermore, the AMOA analogue,
1a, blocked two kainic acid receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 (
K
b
=
19
μM). Unlike the iGluR antagonist (
S)-2-amino-3-[5-
tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [(
S)-ATPO], the corresponding tetrazolyl analogue,
1b, lacks kainic acid receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA receptor subunit GluR2 and a homology model of the kainic acid receptor subunit GluR5, we were able to rationalize the observed structure–activity relationships. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0968-0896 1464-3391 |
DOI: | 10.1016/j.bmc.2005.06.024 |