Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLUK5 kainate receptor antagonists

J Med Chem. 2007 Apr 5;50(7):1558-70. doi: 10.1021/jm061041u. Epub 2007 Mar 10.

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

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / analogs & derivatives*
  • Alanine / chemical synthesis
  • Alanine / chemistry
  • Alanine / pharmacology
  • Animals
  • Animals, Newborn
  • Binding Sites
  • Calcium / metabolism
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • In Vitro Techniques
  • Ligands
  • Models, Molecular
  • Motor Neurons / drug effects
  • Motor Neurons / physiology
  • Nerve Fibers, Unmyelinated / drug effects
  • Nerve Fibers, Unmyelinated / physiology
  • Protein Conformation
  • Pyrimidinones / chemical synthesis*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Rats
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / genetics
  • Receptors, AMPA / physiology
  • Receptors, Kainic Acid / antagonists & inhibitors*
  • Receptors, Kainic Acid / genetics
  • Receptors, Kainic Acid / physiology
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Spinal Nerve Roots / drug effects
  • Spinal Nerve Roots / physiology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis
  • Uracil / chemistry
  • Uracil / pharmacology

Substances

  • 1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-ylmethyl)-5-methylpyrimidine-2,4-dione
  • Gluk1 kainate receptor
  • Ligands
  • Pyrimidinones
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Recombinant Proteins
  • willardiine
  • Uracil
  • Alanine
  • Calcium