Takagi K, Hasegawa T, Kuzuya T, Ogawa K, Watanabe T, Satake T, Miyamoto K, Wakusawa S, Koshiura R
Second Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Jpn J Pharmacol. 1988 Apr;46(4):373-8. doi: 10.1254/jjp.46.373.
Structure-activity studies were carried out to compare the relaxant effects of various xanthine derivatives synthesized by substitution of the alkyl groups of the N3 position in the xanthine molecule. We evaluated the relaxant effects and the inhibitory activities on c-AMP phosphodiesterase (PDE) in tracheal smooth muscle isolated from guinea pigs. A comparative study on their pharmacokinetic characteristics was also carried out in rabbits. Dose-dependent relaxant effects were observed, and the relaxant effect of propylxanthine was nearly equal to the effects of butyl- and isobutylxanthines. Based on the estimation of the Ki values for PDE inhibition, it was found that butylxanthine is a potent inhibitor of PDE. There was good correlation between the alkyl chain length and the Ki value of these derivatives. The results showed that the alkyl chain length plays an important role in the inhibition of PDE. There were no significant differences in the volume of distribution, although the half-life showed significant differences. It is likely that the half-lives of these derivatives are affected by their chain lengths. The present study indicated that butylxanthine may be a new candidate as a bronchodilator. However, clinical studies have to be carried out to compare its efficacy and adverse effects with those of existing bronchodilators such as theophylline.
开展了结构-活性研究，以比较通过取代黄嘌呤分子中N3位的烷基而合成的各种黄嘌呤衍生物的松弛作用。我们评估了从豚鼠分离的气管平滑肌中对c-AMP磷酸二酯酶（PDE）的松弛作用和抑制活性。还在兔子身上对它们的药代动力学特征进行了比较研究。观察到剂量依赖性的松弛作用，丙基黄嘌呤的松弛作用几乎与丁基和异丁基黄嘌呤的作用相当。根据对PDE抑制的Ki值估计，发现丁基黄嘌呤是一种有效的PDE抑制剂。这些衍生物的烷基链长度与Ki值之间存在良好的相关性。结果表明，烷基链长度在PDE抑制中起重要作用。分布容积没有显著差异，尽管半衰期显示出显著差异。这些衍生物的半衰期可能受其链长度的影响。本研究表明，丁基黄嘌呤可能是一种新的支气管扩张剂候选药物。然而，必须进行临床研究以比较其与现有支气管扩张剂如茶碱的疗效和不良反应。
