Structure-activity relationship studies on N-3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists

摘要

N-3-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. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLU(K5)-containing kainate receptors (K-D 0.105 +/- 0.007 mu M vs kainate on native GLU(K5); K-D 71.4 +/- 8.3 mu M vs (S)-5-fluorowillardiine on native AMPA receptors). On recombinant human GLU(K5), GLU(K5)/GLU(K6), and GLU(K5)/GLU(K2), KB values of 0.12 +/- 0.03, 0.12 +/- 0.01, and 0.18 +/- 0.02 mu M, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLU(K6) or GLU(K7) kainate receptors or homomeric GLU(A1-4) AMPA receptors (IC50 values > 100 mu M). Thus, 43 is a potent and selective GLU(K5) receptor antagonist.