Lütjens Henning, Zickgraf Andrea, Figler Heidi, Linden Joel, Olsson Ray A, Scammells Peter J
Centre for Chiral and Molecular Technologies, Deakin University, Geelong, Victoria, 3217, Australia.
J Med Chem. 2003 May 8;46(10):1870-7. doi: 10.1021/jm020295m.
2-Amino-3-aroylthiophenes are agonist allosteric enhancers (AE) at the A(1) adenosine receptor (A(1)AR). Here we report the syntheses of three kinds of novel 2-aminothiophenes and assays of their AE activity at the human A(1)AR (hA(1)AR), namely, (1) 2-amino-4,5-diphenylthiophene-3-carboxylates, 3a-h, (2) 2-amino-3-benzoyl-4,5-diphenylthiophenes, 7a-p, and (3) 2-amino-5-bromo-3-benzoyl-4-phenylthiophenes, 10a-h. An in vitro assay employing the A(1)AR agonist [(125)I]ABA and membranes from CHO-K1 cells stably expressing the hA(1)AR measured an index of AE activity, the ability of a candidate AE to stabilize the agonist-A(1)AR-G protein ternary complex, scored as the percentage of ternary complex remaining after 10 min of dissociation initiated by CPX and GTPgammaS. The AE activity score of 2-amino-4,5-dimethyl-3-(3-trifluoromethylbenzoyl)thiophene (PD 81,723), which was 19%, served as a standard for comparison. Two 3-carboxythiophene 3-trifluoromethylbenzyl esters, 3d (49%) and 3f (63%), had substantial AE activity. The 3-(1-naphthoyl) substituent of 7e (52%) also supported AE activity. Compounds in series 3 tended to be more potent, 10a and 10c having scores of 91 and 80%, respectively. The activity of 2-amino-5-bromo-3-ethoxycarbonyl-4-(3-nitrophenyl)thiophene, 10h (26%), is an exception to the rule that a 3-ethoxycarbonyl substituent cannot support AE activity.
2-氨基-3-芳酰基噻吩是A(1)腺苷受体（A(1)AR）的变构激动剂增强剂（AE）。在此，我们报告了三种新型2-氨基噻吩的合成及其在人A(1)AR（hA(1)AR）上的AE活性测定，即：（1）2-氨基-4,5-二苯基噻吩-3-羧酸酯，3a-h；（2）2-氨基-3-苯甲酰基-4,5-二苯基噻吩，7a-p；（3）2-氨基-5-溴-3-苯甲酰基-4-苯基噻吩，10a-h。采用A(1)AR激动剂[(125)I]ABA和稳定表达hA(1)AR的CHO-K1细胞膜进行的体外测定，测量了AE活性指标，即候选AE稳定激动剂-A(1)AR-G蛋白三元复合物的能力，通过CPX和GTPγS引发解离10分钟后剩余三元复合物的百分比来评分。2-氨基-4,5-二甲基-3-(3-三氟甲基苯甲酰基)噻吩（PD 81,723）的AE活性评分为19%，作为比较标准。两种3-羧基噻吩3-三氟甲基苄酯，3d（49%）和3f（63%），具有显著的AE活性。7e的3-(1-萘甲酰基)取代基（52%）也支持AE活性。系列3中的化合物往往更有效，10a和10c的评分分别为91%和80%。2-氨基-5-溴-3-乙氧基羰基-4-(3-硝基苯基)噻吩，10h（26%）的活性是3-乙氧基羰基取代基不能支持AE活性这一规则的例外。
