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

Willardiine derivatives with an N-3-benzyl substituent bearing an acidic group have been synthesized with the aim of producing selective antagonists for GLU(K5)-containing kainate receptors. UBP296 was found to be a potent and selective antagonist of native GLU(K5)-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 GLU(K5) in homomeric or heteromeric forms. In radioligand displacement binding studies, the willardiine analogues displaced [H-3]kainate binding with IC50 values > 100 muM at rat GLU(K6), GLU(K2) or GLU(K6)/GLU(K2). An explanation of the GLU(K5) selectivity of UBP296 was obtained using homology models of the antagonist bound forms of GLU(K5) and GLU(K6). 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 GLU(K5)-containing kainate receptors in mossy fibre LTP. In conclusion, UBP296 is the most potent and selective antagonist of GLU(K5)-containing kainate receptors so far described. (C) 2004 Elsevier Ltd. All rights reserved.