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Characterisation of UBP296: A Novel, Potent and Selective Kainate Receptor Antagonist

Characterisation of UBP296: A Novel, Potent and Selective Kainate Receptor Antagonist

Julia C A More, 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, etc.

Neuropharmacology. 2004 Jul;47(1):46-64.

PMID: 15165833

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP745055918	UBP302		745055-91-8	Price

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