887246-89-1Relevant articles and documents
Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists
Dolman, Nigel P.,More, Julia C. A.,Alt, Andrew,Knauss, Jody L.,Troop, Helen M.,Bleakman, David,Collingridge, Graham L.,Jane, David E.
, p. 2579 - 2592 (2007/10/03)
N3-Substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and kainate receptor antagonists. In an attempt to improve the potency and selectivity of these AMPA and kainate receptor antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (5′)-1-(2-Amino-2-carboxyethyl)-3-(2- carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLUK5-containing kainate receptors (KD 0.105 ± 0.007 μM vs kainate on native GLUK5; KD 71.4 ± 8.3 μM vs (S)-5- fluorowillardiine on native AMPA receptors). On recombinant human GLU K5, GLUK5/GLUK6, and GLUK5/GLU K2, KB values of 0.12 ± 0.03, 0.12 ± 0.01, and 0.18 ± 0.02 μM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLUK6 or GLUK7 kainate receptors or homomeric GLUA1-4 AMPA receptors (IC50 values > 100 μM). Thus, 43 is a potent and selective GLUK5 receptor antagonist.
