Characterisation of UBP296: a novel, potent and selective kainate receptor antagonist

Neuropharmacology. 2004 Jul;47(1):46-64. doi: 10.1016/j.neuropharm.2004.03.005.


Willardiine derivatives with an N3-benzyl substituent bearing an acidic group have been synthesized with the aim of producing selective antagonists for GLUK5-containing kainate receptors. UBP296 was found to be a potent and selective antagonist of native GLUK5-containing kainate receptors in the spinal cord, with activity residing in the S enantiomer (UBP302). In cells expressing human kainate receptor subunits, UBP296 selectively depressed glutamate-induced calcium influx in cells containing GLUK5 in homomeric or heteromeric forms. In radioligand displacement binding studies, the willardiine analogues displaced [3H]kainate binding with IC50 values >100 microM at rat GLUK6, GLUK2 or GLUK6/GLUK2. An explanation of the GLUK5 selectivity of UBP296 was obtained using homology models of the antagonist bound forms of GLUK5 and GLUK6. In rat hippocampal slices, UBP296 reversibly blocked ATPA-induced depressions of synaptic transmission at concentrations subthreshold for affecting AMPA receptor-mediated synaptic transmission directly. UBP296 also completely blocked the induction of mossy fibre LTP, in medium containing 2 mM (but not 4 mM) Ca2+. These data provide further evidence for a role for GLUK5-containing kainate receptors in mossy fibre LTP. In conclusion, UBP296 is the most potent and selective antagonist of GLUK5-containing kainate receptors so far described.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / analogs & derivatives
  • Alanine / chemical synthesis
  • Alanine / pharmacology
  • Animals
  • Animals, Newborn
  • Cell Line
  • Female
  • Humans
  • Kainic Acid / pharmacology
  • Kinetics
  • Male
  • Methoxyhydroxyphenylglycol / analogs & derivatives*
  • Methoxyhydroxyphenylglycol / pharmacology
  • N-Methylaspartate / pharmacology
  • Nerve Fibers / drug effects
  • Nerve Fibers / physiology*
  • Protein Subunits / drug effects
  • Protein Subunits / physiology
  • Rats
  • Rats, Wistar
  • Receptors, Glutamate / drug effects
  • Receptors, Glutamate / physiology
  • Receptors, Kainic Acid / antagonists & inhibitors*
  • Spinal Nerve Roots / drug effects
  • Spinal Nerve Roots / physiology*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • Protein Subunits
  • Receptors, Glutamate
  • Receptors, Kainic Acid
  • UBP296
  • Methoxyhydroxyphenylglycol
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Alanine
  • Kainic Acid
  • 3,4-dihydroxyphenylglycol