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Development of novel cardiotonic agents

新型强心剂的开发

基本信息

批准号：
04557009
负责人：
ENDOH Masao
金额：
$ 7.42万
依托单位：
Yamagata University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04557009/
关键词：
OPC-18790 OPC-8212 positive inotropic effect cyclic AMP Ca^<2+> sensitizers intracelluar Ca^<2+>Org 9731 mechanism of action of cardiotonics Org30029 Org9731 新しい強心薬 Denopamine Caセンシタイザー CAMP PDE-III阻害薬 Y-20487 カルバコール

项目摘要

The purpose of the study was to elucidate the mechanism of action of novel cardiotonic agents to provide basic information about useful for clinical application of these agents. Among new compounds investigated, Org 30029 [N-hydroxy-5,6-dimethoxybenzo [b] thiophene-2-carboximide hydrochloride] was the agent with most efficacious positive inotropic effect (PIE), which was mainly due to an increase in Ca^<2+> sensitivity of myofibrils. Because agents belonging to this class (Ca^<2+> sensitizer) neither require activation energy nor cause Ca^<2+> overload, they may provide beneficial clinical procedures to cure the patients with heart failure. Org 3731 with a slight modification of chemical structure of Org 30029 had much less Ca^<2+> sensitizing action and acted mainly by PDE inhibition, indicating that the site of these actions may possess a closely related characteristic. Another result obtained are concerned with the mechanism of action of PDE III inhibitors in intact cardiac muscle. … More These are summarized as follows : 1) PDE isozymes involved in cAMP hydrolysis in mammalian cardiac muscle show a wide range of species dependent variation ; 2) PDE inhibitors have a dual action, i.e., a direct PIE and the action to potentiate the PIE of adrenoceptor activation. The former action requires much higher concentration than the latter, which has a crucial meaning in clinical application of these agents ; 3) some novel compounds such as vesnarinone and pimobendan possess ancillary actions in addition to PDE inhibition. Since both agents have beneficial effects on the prognosis (survival rate) of the patients with severe heart failure, it is important to differentiate which mechanisms contribute most significantly to the clinical usefulness ; 4) while cAMP decreases the Ca^<2+> sensitivity of myofibrils in association with phosphorylation of troponin I,PDE III inhibitors did not produce such an action in contrast to beta- agonists, implying the intracellular compartmentation of cAMP in myocardial cells. Pathophysiological relevance of this difference under clinical setting is unknown for the time being and requires further study. Several novel agents have been developed, but there are no agents so far to replace digitalis in the treatment of heart failure. Further intensive effort will be required including evaluation of the clinical usefulness of these agents by careful investigation and synthesis of new agents with novel mechanism. Less

本研究旨在阐明新型强心药物的作用机制，为该类药物的临床应用提供基础资料。在所研究的新化合物中，N-羟基-5，6-二甲氧基苯并[B]噻吩-2-甲酰胺盐酸盐是具有最有效的正性肌力作用（PIE）的药物，这主要是由于肌原纤维对Ca^2+的敏感性增加。由于属于这类药物（Ca^2+增敏剂）既不需要活化能，也不引起Ca^2+过载，因此它们可以提供有益的临床方法来治愈心力衰竭患者。化学结构稍有改变的化合物3731对Ca^2+的增敏作用明显减弱，主要通过抑制PDE起作用，表明这些作用的位点可能具有密切相关的特征。获得的另一结果涉及PDE III抑制剂在完整心肌中的作用机制。 ...更多信息这些总结如下：1）参与哺乳动物心肌中cAMP水解的PDE同工酶显示出广泛的物种依赖性变异; 2）PDE抑制剂具有双重作用，即，直接PIE和增强肾上腺素受体激活的PIE的作用。前者作用所需的浓度远高于后者，这对该类药物的临床应用具有重要意义; 3）一些新化合物如维司力酮、匹莫苯等除了PDE抑制作用外，还具有辅助作用。由于这两种药物对预后都有有益的影响，（存活率），重要的是区分哪些机制对临床有用性最有意义; 4）cAMP降低肌原纤维对Ca^<2+>的敏感性与肌钙蛋白I的磷酸化有关，而PDE III抑制剂与β-激动剂相比不产生这种作用，这意味着心肌细胞中cAMP的细胞内区室化。这种差异在临床环境下的病理生理相关性目前尚不清楚，需要进一步研究。已经开发了几种新的药物，但到目前为止还没有药物可以取代洋地黄治疗心力衰竭。需要进一步加强努力，包括通过仔细研究和合成具有新机制的新药物来评估这些药物的临床有用性。少