Partial adenosine A1 receptor agonists for cardiovascular therapies

Abstract

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.

Fig. 1

A1 receptor activation by a full or partial agonist or blockade by an antagonist in the presence of adenosine; A1R adenosine A1 receptor

Fig. 2

Chemical structure of capadenoson

Fig. 3

Chemical synthesis of a none-purinergic adenosine A1 agonist

Fig. 4

Chemical synthesis of capadenoson

Fig. 5

Stimulation (in percent) of [³⁵S]GTPγS binding by capadenoson (circle) or CCPA (triangle) to human cortex membranes. Maximal CCPA stimulation is set as 100%. Shown are means ± SEM

Fig. 6

Reduction of heart rate by increasing concentrations of capadenoson (black bars) and CCPA (white bars) in isolated rat Langendorff hearts. Shown are means ± SEM

Fig. 7

Dose-dependent reduction of infarct size by capadenoson in an ischemia–reperfusion injury rat model. Capadenoson was given in mg/kg i.v. Shown are means ± SEM. n = 9–18. *p < 0.05; **p < 0.01 vs. placebo