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首页> 外文期刊>American Journal of Physiology >Novel N6-substituted adenosine 5'-N-methyluronamides with high selectivity for human adenosine A3 receptors reduce ischemic myocardial injury.
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Novel N6-substituted adenosine 5'-N-methyluronamides with high selectivity for human adenosine A3 receptors reduce ischemic myocardial injury.

机译：对人腺苷A3受体具有高选择性的新型N6-取代腺苷5'-N-甲基脲酰胺可减少缺血性心肌损伤。

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摘要

We recently reported the identification of a novel human adenosine A3 receptor-selective agonist, (2S,3S,4R,5R)-3-amino-5-[6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzy lamino]purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide (CP-608,039), with 1,260-fold selectivity for the human A3 versus human A1 receptor (DeNinno et al., J Med Chem 46: 353-355, 2003). However, because the modest (20-fold) rabbit A3 receptor selectivity of CP-608,039 precludes demonstration of A3-mediated cardioprotection in rabbit models, we identified another member of this class, (2S,3S,4R,5R)-3-amino-5-[6-(2,5-dichlorobenzylamino)purin-9-yl]-4-hydroxyt etrahydrofuran-2-carboxylic acid methylamide (CP-532,903), which both retained human A3 receptor selectivity (210-fold; human A3/human A1 Ki: 23/4,800 nM) and had improved rabbit A3 receptor selectivity (90-fold; rabbit A3/rabbit A1 Ki: 23/2,000 nM). Infarct size was measured in Langendorff hearts or in vivo after 30 min of regional ischemia and 120 min of reperfusion. Five-minute perfusion with CP-532,903 before ischemia-reperfusion elicited a concentration-dependent reduction in infarct size in isolated hearts (EC50: 0.97 nM; maximum reduction in infarct size: 77%, P < 0.05 vs. control). Furthermore, administration of CP-532,903 (150 nM) at reperfusion also significantly reduced infarct size by 64% (P < 0.05 vs. control), which was not different (P > or = 0.05) from the cardioprotection provided by the same concentration of drug given before ischemia. The selective rabbit A1 receptor antagonist BWA1433 did not affect CP-532,903-dependent cardioprotection. In vivo, CP-532,903 (1 mg/kg) reduced infarct size by 50% in the absence of significant hemodynamic effects (mean arterial pressure, heart rate, rate-pressure product). CP-532,903 and CP-608,039 represent a novel class of human A3 receptor-selective agonists that may prove suitable for investigation of the clinical cardioprotective efficacy of A3 receptor activation.
机译：我们最近报道了一种新型人腺苷A3受体选择性激动剂（2S，3S，4R，5R）-3-氨基-5- [6- [5-氯-2-（3-甲基异恶唑-5-基甲氧基） ）亚氨基]嘌呤-9-基] -4-羟基四氢呋喃-2-羧酸甲基酰胺（CP-608,039），对人A3的选择性是对人A1受体的1,260倍（DeNinno等人，J Med Chem 46： 353-355，2003）。但是，由于CP-608,039具有适度（20倍）的兔A3受体选择性，无法在兔模型中证明A3介导的心脏保护作用，因此我们确定了该类别的另一成员（2S，3S，4R，5R）-3-氨基-5- [6-（2,5-二氯苄氨基）嘌呤-9-基] -4-羟基叔氢呋喃-2-羧酸甲酰胺（CP-532,903），两者均保留了人类A3受体的选择性（210倍;人类A3 /人A1 Ki：23 / 4,800 nM），并具有改善的兔A3受体选择性（90倍;兔A3 /兔A1 Ki：23 / 2,000 nM）。在局部缺血30分钟和再灌注120分钟后，在Langendorff心脏或体内测量梗死面积。在缺血再灌注之前，用CP-532,903进行五分钟灌注可引起离体心脏梗死面积的浓度依赖性减小（EC50：0.97 nM;最大梗死面积减小：77％，与对照相比，P <0.05）。此外，在再灌注时给予CP-532,903（150 nM）也可将梗死面积显着减少64％（与对照组相比，P <0.05），与相同浓度的心脏保护所提供的心脏保护作用无差异（P>或= 0.05）。缺血前给予药物。选择性兔A1受体拮抗剂BWA1433不影响CP-532,903依赖性的心脏保护作用。在体内，CP-532,903（1 mg / kg）在没有明显的血液动力学影响（平均动脉压，心率，心率-血压乘积）的情况下将梗死面积减少了50％。 CP-532,903和CP-608,039代表一类新型的人类A3受体选择性激动剂，可证明适用于研究A3受体激活的临床心脏保护功效。

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