Characterisation of UBP296: a novel, potent and selective kainate receptor antagonist.
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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Julia C A
JC
Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Nistico
Robert
R
Dolman
Nigel P
NP
Clarke
Vernon R J
VR
Alt
Andrew J
AJ
Ogden
Ann M
AM
Buelens
Floris P
FP
Troop
Helen M
HM
Kelland
Eve E
EE
Pilato
Fabio
F
Bleakman
David
D
Bortolotto
Zuner A
ZA
Collingridge
Graham L
GL
Jane
David E
DE
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
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