Baraldi P G, Cacciari B, Pineda de Las Infantas M J, Romagnoli R, Spalluto G, Volpini R, Costanzi S, Vittori S, Cristalli G, Melman N, Park K S, Ji X D, Jacobson K A
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
J Med Chem. 1998 Aug 13;41(17):3174-85. doi: 10.1021/jm980147p.
A new series of 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-D-ribofuranuronamide++ +-b earing N-arylureas or N-arylcarboxamido groups at the purine 6 position and N-arylureas combined with halogens or alkynyl chains at the 2 position have been synthesized and tested for affinity at A1 and A2A adenosine receptors in rat brain membranes and at cloned rat A3 receptors expressed in CHO cells. The derivatives contained the 5' substituent found in the potent, nonselective agonist 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-beta-D-ribofuranuronamide++ + (NECA). While the carboxamido derivatives (9-13) showed affinity for A1 receptors, the urea derivatives (30-45) showed different degrees of affinity and selectivity for the A3 adenosine receptor subtype. In particular the derivative bearing a p-sulfonamidophenyl-urea at the 6 position, 31 showed a high affinity (Ki = 9 nM) and selectivity for the A3 receptors compared to that of the reference compound 1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-be ta-D-ribofuranuronamide (IB-MECA). Furthermore, the importance of the stereochemistry in the interaction of these ligands at the rat A3 adenosine receptors has been evaluated by introducing a chiral chain at the 6 position. The introduction of halogens or alkynyl chains at the purine 2 position of selected ureas did not give the expected enhancement of potency at A2A and/or A3 receptors but rather showed a dramatic reduction of A2A affinity, resulting in compounds with good A2A/A3 selectivity. For example, the 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)-6-(4-methoxyphenylurea) derivative 61 showed the capability to bind simultaneously to A1 and A3 receptor subtypes, excluding the A2A receptor. Compound 31 was shown to be an agonist, 9-fold more potent than NECA, at A3 receptors in rat RBL-2H3 mast cell membranes through stimulation of binding of [35S]GTP-gamma-S.
已合成了一系列新的1-(6-氨基-9H-嘌呤-9-基)-1-脱氧-N-乙基-β-D-呋喃核糖脲酰胺，其嘌呤6位带有N-芳基脲或N-芳基甲酰胺基，2位的N-芳基脲与卤素或炔基链相连，并测试了它们对大鼠脑膜中A1和A2A腺苷受体以及在CHO细胞中表达的克隆大鼠A3受体的亲和力。这些衍生物含有强效非选择性激动剂1-(6-氨基-9H-嘌呤-9-基)-1-脱氧-N-乙基-β-D-呋喃核糖脲酰胺（NECA）中的5'取代基。虽然甲酰胺基衍生物（9-13）对A1受体有亲和力，但脲衍生物（30-45）对A3腺苷受体亚型表现出不同程度的亲和力和选择性。特别是在6位带有对磺酰胺基苯基脲的衍生物31，与参考化合物1-[6-[[(3-碘苯基)甲基]氨基]-9H-嘌呤-9-基]-1-脱氧-N-甲基-β-D-呋喃核糖脲酰胺（IB-MECA）相比，对A3受体显示出高亲和力（Ki = 9 nM）和选择性。此外，通过在6位引入手性链，评估了这些配体在大鼠A3腺苷受体相互作用中立体化学的重要性。在所选脲的嘌呤2位引入卤素或炔基链并未如预期那样增强在A2A和/或A3受体上的效力，反而显示出A2A亲和力急剧降低，从而得到具有良好A2A/A3选择性的化合物。例如，2-(3-羟基-3-苯基-1-丙炔-1-基)-6-(4-甲氧基苯基脲)衍生物61显示出同时结合A1和A3受体亚型的能力，而不与A2A受体结合。化合物31在大鼠RBL-2H3肥大细胞膜的A3受体上通过刺激[35S]GTP-γ-S的结合被证明是一种激动剂，其效力比NECA高9倍。
