A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity.
A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity.
复制标题
DOI：
10.1021/jm50001a001
复制
发表时间：
1985-05
影响因子：
7.3
通讯作者：
R. Weishaar;M. Cain;J. Bristol
中科院分区：
文献类型：
--
作者：
R. Weishaar;M. Cain;J. Bristol
除了几个明显的例外，在汤普森于1971年发现大脑中不止一种磷酸二酯酶之后的十年中，对磷酸二酯酶的多种分子形式的兴趣仍然相对休眠。然而，在过去的几年中，已经鉴定了超过20种新的药剂，其对存在于不同细胞内的各种分子形式的磷酸二酯酶发挥选择性抑制作用。此外，几项研究已经证明，这些药物可以产生环AMP和环GMP的离散变化，这是“第一代”磷酸二酯酶抑制剂如茶碱所不具有的作用。这个观点的目的是提供一些清晰的选择性磷酸二酯酶抑制剂这一快速发展的领域。因此，我们试图根据其动力学性质、底物特异性等来表征存在于各种组织和细胞中的不同形式的磷酸二酯酶，并且还表征那些已显示出选择性或非选择性抑制磷酸二酯酶活性的主要类别的药剂。此外，我们已经描述了几个治疗领域，其中选择性磷酸二酯酶抑制剂可能被证明是有效的，特别注意那些领域，其中选择性磷酸二酯酶抑制剂已经显示出发挥有益的作用，即，刺激心肌收缩，抑制介质释放，抑制血小板聚集。虽然集中在这三个领域，但很明显，选择性磷酸二酯酶抑制剂的潜在治疗效用可以想象地延伸到环核苷酸的调节可以具有期望效果的几个其他领域，包括癌症化疗、镇痛、抑郁症的治疗、帕金森病以及学习和记忆障碍。例如，选择性III型磷酸二酯酶抑制剂咯利普兰已显示出拮抗利血平诱导的体温过低，并且还增强育亨宾的致死性，这两个测试指示抗抑郁活性。此外，将选择性PDE III抑制剂Ro 20-1724显微注射到大鼠脑干中已显示产生镇痛作用。（400字处截断摘要）
With several notable exceptions, interest in the area of multiple molecular forms of phosphodiesterase remained relatively dormant during the decade following Thompson's discovery of more than one phosphodiesterase in brain in 1971. Within the last several years, however, over 20 novel agents have been identified that exert selective inhibitory effects on the various molecular forms of phosphodiesterase present within different cells. In addition, several studies have documented that such agents can produce discrete changes in cyclic AMP and cyclic GMP, an action that is not shared by "first generation" phosphodiesterase inhibitors such as theophylline. The purpose of this Perspective is to provide some clarity to this rapidly evolving area of selective phosphodiesterase inhibitors. Thus, we have attempted to characterize the different forms of phosphodiesterase present in various tissues and cells according to their kinetic properties, substrate specificity, etc. and also to characterize those major classes of agents that have been shown to inhibit phosphodiesterase activity, whether selectively or nonselectively. In addition, we have described several therapeutic areas wherein selective phosphodiesterase inhibitors might prove efficacious, paying particular attention to those areas in which selective phosphodiesterase inhibitors have already been shown to exert beneficial effects, namely, stimulation of myocardial contractility, inhibition of mediator release, and inhibition of platelet aggregation. Although focusing on these three areas, it is obvious that the potential therapeutic utility of selective phosphodiesterase inhibitors could conceivably extend to several other areas in which modulation of cyclic nucleotides can have desirable effects, including cancer chemotherapy, analgesia, the treatment of depression, Parkinson's disease, and learning and memory disorders. For example, the selective type III phosphodiesterase inhibitor rolipram has been shown to antagonize reserpine-induced hypothermia and also to potentiate yohimbine lethality, two tests that are indicative of antidepressant activity. In addition, microinjection of the selective PDE III inhibitor Ro 20-1724 into the rat brain stem has been shown to produce analgesia.(ABSTRACT TRUNCATED AT 400 WORDS)