Partial adenosine A1 receptor agonists for cardiovascular therapies
Partial adenosine A1 receptor agonists for cardiovascular therapies
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DOI：
10.1007/s11302-011-9274-3
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发表时间：
2012-02-01
影响因子：
3.5
通讯作者：
Nell, Peter G.
中科院分区：
文献类型：
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作者：
Albrecht-Kuepper, Barbara E.;Leineweber, Kirsten;Nell, Peter G.
腺苷是一种嘌呤核苷，以严格控制的浓度存在于所有细胞中。它对全身和心脏都有许多不同的生理作用。腺苷激活四个G蛋白偶联受体A1、A2a、A2b和A3。心肌A1受体的激活已被证明可抑制与缺血和再灌注损伤相关的各种心肌病理，包括顿抑、心律失常、冠状动脉和心功能不全、急性心肌梗死、细胞凋亡和慢性心力衰竭，这意味着有几种新的心血管疗法可用于治疗疾病，如心绞痛、心律控制、急性冠状动脉综合征期间的缺血性损伤或心力衰竭。然而，在这些适应症中使用完整的A1受体激动剂的主要问题是心脏和心脏外效应的广泛生理谱。当考虑使用完整的A1受体激动剂时，期望的A1受体介导的保护和再生心血管效应可能会被意外的副作用反向调节。这些效应可被部分A1激动剂克服。部分A1激动剂只能用来触发受体激活的部分生理反应，这取决于内源性腺苷水平和不同组织中的受体储备。CV-Treateutics报道了一种部分A1受体激动剂CVT-3619，最近又发表了另一种部分A1受体激动剂VCP28。这两种化合物都是腺苷的衍生物。腺苷类A1受体激动剂通常具有半衰期短、生物利用度低的缺点，不适合慢性口服治疗。我们确定了第一个药代动力学最优的非腺苷类A1受体部分激动剂(S)，每天口服一次，并在临床前和临床研究中表征了A1受体激动剂(S)的部分特征。
Adenosine, a purine nucleoside, is present in all cells in tightly regulated concentrations. It has many different physiological effects in the whole body and in the heart. Adenosine activates four G protein-coupled receptors A1, A2a, A2b, and A3. Activation of myocardial A1 receptors has been shown to inhibit a variety of myocardial pathologies associated with ischemia and reperfusion injury, including stunning, arrhythmogenesis, coronary and ventricular dysfunction, acute myocardial infarction, apoptosis, and chronic heart failure, implying several options for new cardiovascular therapies for diseases, like angina pectoris, control of cardiac rhythm, ischemic injury during an acute coronary syndrome, or heart failure. However, the main issue of using full A1 receptor agonists in such indications is the broad physiologic spectrum of cardiac and extracardiac effects. Desired A1 receptor-mediated protective and regenerative cardiovascular effects might be counter-regulated by unintended side effects when considering full A1 receptor agonists. These effects can be overcome by partial A1 agonists. Partial A1 agonists can be used to trigger only some of the physiological responses of receptor activation depending on endogenous adenosine levels and on receptor reserve in different tissues. CV-Therapeutics reported the identification of a partial A1 receptor agonist CVT-3619, and recently, another partial A1 receptor agonist VCP28 was published. Both compounds are adenosine derivatives. Adenosine-like A1 receptor agonists often have the drawback of a short half-life and low bioavailability, making them not suitable for chronic oral therapy. We identified the first non-adenosine-like partial A1 receptor agonist(s) with pharmacokinetics optimal for oral once daily treatment and characterized the qualities of the partial character of the A1 receptor agonist(s) in preclinical and clinical studies.