Abstract
Some N3-substituted analogues of willardiine such as 11 and 13 are selective kainate receptor antagonists. In an attempt to improve the potency and selectivity for kainate receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing kainate receptors (KB values of 7 +/- 1 and 5 +/- 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 microM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alanine / analogs & derivatives*
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Alanine / chemical synthesis
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Alanine / chemistry
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Alanine / pharmacology
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Animals
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Animals, Newborn
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Binding Sites
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Calcium / metabolism
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Cell Line
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Crystallography, X-Ray
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Humans
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In Vitro Techniques
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Ligands
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Models, Molecular
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Motor Neurons / drug effects
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Motor Neurons / physiology
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Nerve Fibers, Unmyelinated / drug effects
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Nerve Fibers, Unmyelinated / physiology
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Protein Conformation
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / chemistry
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Pyrimidinones / pharmacology
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Rats
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Receptors, AMPA / antagonists & inhibitors
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Receptors, AMPA / genetics
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Receptors, AMPA / physiology
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Receptors, Kainic Acid / antagonists & inhibitors*
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Receptors, Kainic Acid / genetics
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Receptors, Kainic Acid / physiology
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / genetics
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Spinal Nerve Roots / drug effects
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Spinal Nerve Roots / physiology
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Stereoisomerism
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Structure-Activity Relationship
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Uracil / analogs & derivatives*
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Uracil / chemical synthesis
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Uracil / chemistry
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Uracil / pharmacology
Substances
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1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-ylmethyl)-5-methylpyrimidine-2,4-dione
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Gluk1 kainate receptor
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Ligands
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Pyrimidinones
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Receptors, AMPA
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Receptors, Kainic Acid
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Recombinant Proteins
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willardiine
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Uracil
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Alanine
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Calcium