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.

Characterisation of UBP296: a novel, potent and selective kainate receptor antagonist / J. C., A.; Nistico', ROBERT GIOVANNI; N. P., Dolman; V. R., J.; A. J., Alt; A. M., Ogden; F. P., Buelens; H. M., Troop; E. E., Kelland; F., Pilato; D., Bleakman; Z. A., Bortolotto; G. L., Collingridge; D. E., Jane. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - 47:(2004), pp. 46-64. [10.1016/j.neuropharm.2004.03.005]

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

NISTICO', ROBERT GIOVANNI;
2004

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.
2004
Alanine; analogs /&/ derivatives/chemical synthesis/pharmacology, Animals, Animals; Newborn, Cell Line, Female, Humans, Kainic Acid; pharmacology, Kinetics, Male, Methoxyhydroxyphenylglycol; analogs /&/ derivatives/pharmacology, N-Methylaspartate; pharmacology, Nerve Fibers; drug effects/physiology, Protein Subunits; drug effects/physiology, Rats, Rats; Wistar, Receptors; Glutamate; drug effects/physiology, Receptors; Kainic Acid; antagonists /&/ inhibitors, Spinal Nerve Roots; drug effects/physiology, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; pharmacology
01 Pubblicazione su rivista::01a Articolo in rivista
Characterisation of UBP296: a novel, potent and selective kainate receptor antagonist / J. C., A.; Nistico', ROBERT GIOVANNI; N. P., Dolman; V. R., J.; A. J., Alt; A. M., Ogden; F. P., Buelens; H. M., Troop; E. E., Kelland; F., Pilato; D., Bleakman; Z. A., Bortolotto; G. L., Collingridge; D. E., Jane. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - 47:(2004), pp. 46-64. [10.1016/j.neuropharm.2004.03.005]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/514325
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