Analogues of 3-hydroxyisoxazole-containing glutamate receptor ligands based on the 3-hydroxypyrazole-moiety: design, synthesis and pharmacological characterization.
A series of analogues of the glutamate receptor ligands (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) and AMOA were synthesized in which the 3-hydroxyisoxazole moiety was exchanged for a 3-hydroxypyrazole moiety. This exchange enables further substitution at the additional nitrogen atom in the heterocyclic core. Several of the analogues have activity at AMPA receptors equipotent to the antagonist ATPO, demonstrating that additional substitution can be accommodated in the antagonist binding site. Modelling studies offer an explanation for the pharmacological pattern observed for the compounds and suggest that this scaffold may be developed further to obtain subtype selective antagonists.
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark.
Lars
L
Jørgensen
Birgitte
B
Nielsen
Darryl S
DS
Pickering
Anders S
AS
Kristensen
Karla
K
Frydenvang
Ulf
U
Madsen
Rasmus P
RP
Clausen
D000818:Animals; D018360:Crystallography, X-Ray; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017470:Receptors, Glutamate / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D014981:Xenopus
D007555:Isoxazoles; D008024:Ligands; D011720:Pyrazoles; D017470:Receptors, Glutamate