Dolman Nigel P, More Julia C A, Alt Andrew, Knauss Jody L, Troop Helen M, Bleakman David, Collingridge Graham L, Jane David E
Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.
J Med Chem. 2006 Apr 20;49(8):2579-92. 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. (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.
用多种羧基烷基或羧基苄基取代物对威拉地丁的尿嘧啶环进行N3-取代，可产生AMPA和海人酸受体拮抗剂。为了提高这些AMPA和海人酸受体拮抗剂的效力和选择性，合成了一系列具有不同末端酸性基团和酸间基团间隔基的类似物，并对其进行了药理学表征。(S)-1-(2-氨基-2-羧基乙基)-3-(2-羧基噻吩-3-基甲基)嘧啶-2,4-二酮(43，UBP304)对天然含GLU(K5)的海人酸受体表现出高效力和选择性(K(D)为0.105±0.007 microM，相对于天然GLU(K5)上的海人酸；K(D)为71.4±8.3 microM，相对于天然AMPA受体上的(S)-5-氟威拉地丁)。对于重组人GLU(K5)、GLU(K5)/GLU(K6)和GLU(K5)/GLU(K2)，43的K(B)值分别为0.12±0.03、0.12±0.01和0.18±0.02 microM。然而，43对同聚体GLU(K6)或GLU(K7)海人酸受体或同聚体GLU(A1-4)AMPA受体无活性(IC(50)值>100 microM)。因此，43是一种高效且选择性的GLU(K5)受体拮抗剂。
