title: Characterisation of UBP296: a novel, potent and selective kainate receptor antagonist.
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.
authors.affiliation: Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Julia C A
authors.initials: JC
authors.lastname: More
authors.forename: Robert
authors.initials: R
authors.lastname: Nistico
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Dolman
authors.forename: Vernon R J
authors.initials: VR
authors.lastname: Clarke
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Alt
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ogden
authors.forename: Floris P
authors.initials: FP
authors.lastname: Buelens
authors.forename: Helen M
authors.initials: HM
authors.lastname: Troop
authors.forename: Eve E
authors.initials: EE
authors.lastname: Kelland
authors.forename: Fabio
authors.initials: F
authors.lastname: Pilato
authors.forename: David
authors.initials: D
authors.lastname: Bleakman
authors.forename: Zuner A
authors.initials: ZA
authors.lastname: Bortolotto
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: David E
authors.initials: DE
authors.lastname: Jane
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D005260:Female; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology*; D021122:Protein Subunits / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D000409:Alanine; D007608:Kainic Acid; D008734:Methoxyhydroxyphenylglycol; D016202:N-Methylaspartate; D021122:Protein Subunits; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C490221:UBP296; C010117:3,4-dihydroxyphenylglycol