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.

More, J., Nistico', R.g., Dolman, N., Clarke, V., Alt, A., Ogden, A., et al. (2004). Characterisation of UBP296: A novel, potent and selective kainate receptor antagonist. NEUROPHARMACOLOGY, 47(1), 46-64 [10.1016/j.neuropharm.2004.03.005].

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

NISTICO', ROBERT GIOVANNI;
2004-01-01

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
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
Alanine; Animals; Animals, Newborn; Cell Line; Female; Humans; Kainic Acid; Kinetics; Male; Methoxyhydroxyphenylglycol; N-Methylaspartate; Nerve Fibers; Protein Subunits; Rats; Rats, Wistar; Receptors, Glutamate; Receptors, Kainic Acid; Spinal Nerve Roots; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
More, J., Nistico', R.g., Dolman, N., Clarke, V., Alt, A., Ogden, A., et al. (2004). Characterisation of UBP296: A novel, potent and selective kainate receptor antagonist. NEUROPHARMACOLOGY, 47(1), 46-64 [10.1016/j.neuropharm.2004.03.005].
More, J; Nistico', Rg; Dolman, N; Clarke, V; Alt, A; Ogden, A; Buelens, F; Troop, H; Kelland, E; Pilato, F; Bleakman, D; Bortolotto, Z; Collingridge, G; Jane, D
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
Neuph'04UBP.pdf

solo utenti autorizzati

Descrizione: Characterisation of UBP296; a novel, potent and selective kainate receptor antagonist
Licenza: Copyright dell'editore
Dimensione 512.18 kB
Formato Adobe PDF
512.18 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/133219
Citazioni
  • ???jsp.display-item.citation.pmc??? 34
  • Scopus 87
  • ???jsp.display-item.citation.isi??? 84
social impact