| Autor: |
More JC; Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK., Nistico R, Dolman NP, Clarke VR, Alt AJ, Ogden AM, Buelens FP, Troop HM, Kelland EE, Pilato F, Bleakman D, Bortolotto ZA, Collingridge GL, Jane DE |
| Jazyk: |
angličtina |
| Zdroj: |
Neuropharmacology [Neuropharmacology] 2004 Jul; Vol. 47 (1), pp. 46-64. |
| DOI: |
10.1016/j.neuropharm.2004.03.005 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
Full Text from ScienceDirect