Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure

Abstract

Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50%. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF.

Purinergic Signaling in the Cardiovascular System

“…Adenosine therapy is cardioprotective for chronic heart failure mediated by A 1 and A 3 receptors. 117 A 1 receptor activation attenuates cardiac hypertrophy and prevents heart failure in a mouse left-ventricular pressure-overload model and in a rat neonatal cardiac myocyte model. 118 K ATP channels are critical for maintaining myocardial perfusion and highenergy phosphates in the failing heart.…”

Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1‐receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction

“…7,8 The reason for the development of a partial adenosine A1-receptor agonist is that the use of full A1-receptor agonists in HF has been limited by undesirable cardiac effects such as negative inotropic, chronotropic, and dromotropic effects, including high-degree atrioventricular (AV) block, in particular with the concomitant use of -blockers. 8 In addition, a full agonist might have undesired extracardiac effects such as anti-diuretic effects (caused by vasoconstriction of the renal afferent arterioles) and neurological effects such as sedation. A partial adenosine A1-receptor agonist might overcome these undesired side effects while preserving the potentially beneficial cardioprotective effects of adenosine, depending on the tissue-specific receptor reserve for determined pharmacological effects and on the effects of endogenous adenosine.…”

Neladenoson Bialanate Hydrochloride: A Prodrug of a Partial Adenosine A1 Receptor Agonist for the Chronic Treatment of Heart Diseases

“…Furthermore, non‐cardiac effects such as decreased neurotransmitter release in the central nervous system (CNS), resulting in sedation, for example, are known to be triggered by full A 1 R agonists. Therefore, partial A 1 R agonists might be beneficial as a new therapeutic option in treating HF . We previously reported that partial A 1 R agonists modulate and trigger primarily favorable pharmacological responses for HF therapy, such as improvement of left ventricular (LV) function and cardioprotection without evoking the adverse effects of full A 1 R agonists .…”