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.

Adenosinergic regulation of binge-like ethanol drinking and associated locomotor effects in male C57BL/6J mice

“…This may reflect different roles for the A 1 and A 2A receptors in voluntary alcohol consumption versus alcohol reinforcement, although future studies should more directly address this possibility. In the context of this systemic administration study, it is also important to note that A 1 and A 2A receptors are present in the periphery, largely regulating cardiovascular and inflammatory processes (Albrecht-Küpper et al, 2012, Deharo et al, 2012, Williams and Cronstein, 2012, Antonioli et al, 2013). Future efforts employing brain-region specific administration will seek to clarify the extent to which the observed effects are mediated by central or perhaps, peripheral effects.…”

Glial adenosine kinase – A neuropathological marker of the epileptic brain

“…As a result, systemic administration of A 1 R agonists or ADK inhibitors successfully attenuates seizure activity (Fredholm, 2003; Jacobson and Gao, 2006; Boison, 2011). However, the use of systemic A 1 R agonists, ADK inhibitors or adenosine as a therapeutic strategy for epilepsy treatment is limited due to negative side effects including bradycardia, vasoconstriction in the kidney and sedation (Albrecht-Kupper et al, 2012). Thus, it is imperative that novel therapeutic approaches, which focally restore normal adenosine levels, are developed for epilepsy treatment.…”

Adenosine A_2A  receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction

“…AR activation inhibits fibroblast proliferation and collagen synthesis,8,9 thus limiting cardiac tissue remodeling and progression to failure. Moreover, activated ARs have favorable regulatory effects on several phenomena associated with ischemic and pressure-overload insults, including cytokine release,10,11 cell death processes,12 and oxidative stress 13,14…”