| Autor: |
Dolman NP; Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom., More JC, Alt A, Knauss JL, Pentikäinen OT, Glasser CR, Bleakman D, Mayer ML, Collingridge GL, Jane DE |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2007 Apr 05; Vol. 50 (7), pp. 1558-70. Date of Electronic Publication: 2007 Mar 10. |
| DOI: |
10.1021/jm061041u |
| Abstrakt: |
Some N3-substituted analogues of willardiine such as 11 and 13 are selective kainate receptor antagonists. In an attempt to improve the potency and selectivity for kainate receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing kainate receptors (KB values of 7 +/- 1 and 5 +/- 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 microM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
