New Inotropic Agents for the Treatment of Heart Failure

描述（由申请人提供）：该项目的目标是开发新的 正性肌力药，以特异性修饰的AMP分子为代表。所有 目前可用正性肌力药物具有显著的不利作用 洋地黄是唯一可口服的正性肌力药。ATP 引起明显的正性肌力作用。ATP受体，称为P2 嘌呤能受体介导其正性肌力作用。 然而，以增强的功效作用于该心脏P2受体的激动剂， 能力和选择性都是缺乏的。初步数据显示， AMP分子的特异性修饰将赋予正性肌力 活性和选择性与血管P2受体。成年大鼠心室 已经开发了心肌细胞和完整心脏模型来确定亲和力 新药物对肌细胞P2受体的作用及其对 完整心脏的各种功能参数。的总体目标 研究是使用这些心脏模型来测试这些特异性修饰的AMP 心脏P2受体的分子。新的化学结构将是 与亲和力和正性肌力活性相关， vs.血管P2受体选择性。这些化合物对 还将测定清醒大鼠的心率和血压。的 研究可能导致潜在有用的新的正性肌力药物， 心力衰竭的治疗

DESCRIPTION (provided by applicant): The goal of the project is to develop new positive inotropes, represented by specifically modified AMP molecules. All of the currently available positive inotropic agents have significant adverse effects with digitalis being the only orally available positive inotrope. ATP causes a pronounced positive inotropic effect. Receptors for ATP, known as P2 purinergic receptor, has been shown to mediate its positive inotropic effect. However, agonists acting at this cardiac P2 receptor with enhanced efficacy, potency and selectivity, are lacking. Preliminary data suggest that certain specific modifications of the AMP molecule will confer positive inotropic activity and selectivity vs. the vascular P2 receptor. Adult rat ventricular myocytes and intact heart model have been developed to determine the affinity and efficacy of new agents at the myocyte P2 receptor and their effects on the various functional parameters in the intact heart. The overall objective of the study is to use these cardiac models to test these specifically modified AMP molecules at the cardiac P2 receptor. New chemical structures will be correlated with the affinity and the positive inotropic activity and cardiac vs. vascular P2 receptor selectivity. The effects of these compounds on the heart rate and blood pressure in conscious rats will also be determined. The studies may lead to potentially useful new positive inotropic agents for the treatment of heart failure.