Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists

Article abstract of DOI:10.1021/jm051086f

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 GLU_K5-containing kainate receptors (K_D 0.105 ± 0.007 μM vs kainate on native GLU_K5; K_D 71.4 ± 8.3 μM vs (S)-5- fluorowillardiine on native AMPA receptors). On recombinant human GLU _K5, GLU_K5/GLU_K6, and GLU_K5/GLU _K2, K_B 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 GLU_K6 or GLU_K7 kainate receptors or homomeric GLU_A1-4 AMPA receptors (IC₅₀ values > 100 μM). Thus, 43 is a potent and selective GLU_K5 receptor antagonist.