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.
Julia C A More  1 ,  Robert Nistico ,  Nigel P Dolman ,  Vernon R J Clarke ,  Andrew J Alt ,  Ann M Ogden ,  Floris P Buelens ,  Helen M Troop ,  Eve E Kelland ,  Fabio Pilato ,  David Bleakman ,  Zuner A Bortolotto ,  Graham L Collingridge ,  David E Jane
Affiliations
  • 1. Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
PMID: 15165833 DOI: 10.1016/j.neuropharm.2004.03.005
Abstract

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.

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