title: Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists.
abstract: 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. (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 microM vs kainate on native GLU(K5); K(D) 71.4 +/- 8.3 microM 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 microM, 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 (IC(50) values > 100 microM). Thus, 43 is a potent and selective GLU(K5) receptor antagonist.
authors.affiliation: Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Dolman
authors.forename: Julia C A
authors.initials: JC
authors.lastname: More
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
authors.forename: Jody L
authors.initials: JL
authors.lastname: Knauss
authors.forename: Helen M
authors.initials: HM
authors.lastname: Troop
authors.forename: David
authors.initials: D
authors.lastname: Bleakman
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: David E
authors.initials: DE
authors.lastname: Jane
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013997:Time Factors; D014498:Uracil / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors*
chemical_list: D000409:Alanine; D011744:Pyrimidinones; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins; D014498:Uracil; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C518061:1-(2-amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione; C002872:willardiine