4 The Adenosine A1 Receptor and its Ligands

Nell, Peter G.; Albrecht-Küpper, Barbara

doi:10.1016/s0079-6468(08)00204-x

Cited by 23 publications

(27 citation statements)

References 134 publications

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“…Optimization of partial adenosine A1 receptor agonists Optimization of partial A1 agonists has been described in great detail by Nell and Albrecht-Küpper [28]. 35 S-GTP binding assay Human frontal lobe was obtained from Analytical Biological Services Inc. (Wilmington, DE, USA).…”

Section: Methodsmentioning

confidence: 99%

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Partial adenosine A1 receptor agonists for cardiovascular therapies

Albrecht-Küpper

Leineweber

Nell

2011

Purinergic Signalling

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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.

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Section: Methodsmentioning

confidence: 99%

“…2) [27,28]. Capadenoson is a partial A1 receptor agonist with an EC 50 of 0.1 nM on human A1 receptors and a selectivity factor of 1,800 vs. A2a, 900 vs. A2b, and no activity on A3 receptors.…”

Section: Introductionmentioning

confidence: 99%

Partial adenosine A1 receptor agonists for cardiovascular therapies

Albrecht-Küpper

Leineweber

Nell

2011

Purinergic Signalling

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“…However, activation of A1R, which primarily couples to (inhibitory or other) G i/o proteins, also slows HR, which is therapeutically exploited in treatment of certain supraventricular arrhythmias, but, in the context of chronic HF, it might constitute an undesirable effect, as it can lead to bradycardias and atrioventricular blocks 61. A partial A1R agonist, capadenoson,62 was very recently shown to improve LV function and prevent progressive cardiac adverse remodeling in a canine chronic HF model 63. Importantly, improvement of LV systolic function seemed to occur early after treatment initiation with capadenoson, and, since the compound is not a full agonist at the A1R, it appears devoid of the HR-lowering complications with which full A1R agonism is hampered 63.…”

Section: Targets For Hf Therapy In Signaling From Other Gpcrsmentioning

confidence: 99%

Current and future G protein-coupled receptor signaling targets for heart failure therapy

Siryk-Bathgate¹,

Dabul²,

Lymperopoulos³

2013

DDDT

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Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of β-blockers and antagonists of the renin–angiotensin–aldosterone system, this devastating disease still carries tremendous morbidity and mortality in the western world. G protein-coupled receptors, such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, ie, myocytes, fibroblasts, and endothelial cells, play crucial roles in regulation of cardiac function in health and disease. Their importance is reflected by the fact that, collectively, they represent the direct targets of over one-third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart failure therapy. Here, we review these possible targets for heart failure therapy that have emerged from studies of cardiac G protein-coupled receptor signaling in health and disease, with a particular focus on the main cardiac G protein-coupled receptor types, ie, the β-adrenergic and the angiotensin II type 1 receptors. We also highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.

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“…Activation of the A1R using “full” agonists, while offering potential therapeutic benefits, is limited by undesirable side effects that include bradycardia, atrio-ventricular (AV) blocks, sedation and anti-diuretic effects. To overcome the side effects of full A1R agonism, efforts were recently placed on tailoring compounds only to the desired pharmacologic efficacy by developing “partial” adenosine A1R agonists that are likely to elicit beneficial therapeutic effects without giving rise to undesirable side effects (4). One such compound is Capadenoson (CAP) (BAY 68-4986), a partial adenosine A1R receptor agonist (4).…”

Section: Introductionmentioning

confidence: 99%

“…To overcome the side effects of full A1R agonism, efforts were recently placed on tailoring compounds only to the desired pharmacologic efficacy by developing “partial” adenosine A1R agonists that are likely to elicit beneficial therapeutic effects without giving rise to undesirable side effects (4). One such compound is Capadenoson (CAP) (BAY 68-4986), a partial adenosine A1R receptor agonist (4). It has high affinity for the A1R and high selectivity over other adenosine receptors with a favorable pharmacokinetic profile evidenced by long half-life and high bioavailability (5).…”

Section: Introductionmentioning

confidence: 99%

Chronic Therapy With a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Function and Remodeling in Dogs With Advanced Heart Failure

Sabbah

Gupta

Kohli

et al. 2013

Circ: Heart Failure

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Background Adenosine (AD) elicits cardioprotection through A1-receptor (A1R) activation. Therapy with AD A1R agonists, however, is limited by undesirable actions of full agonism such as bradycardia. This study examined the effects of capadenoson (CAP), a partial AD A1R agonist, on left ventricular (LV) function and remodeling in dogs with heart failure (HF). Methods and Results 12 dogs with microembolization-induced HF were randomized to 12 weeks oral therapy with CAP (7.5 mg Bid, n=6) or to no therapy (Control, n=6). LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), plasma norepinephrine (NE) and n-terminal pro-brain natriuretic peptide (nt-pro BNP) were measured before (PRE) and 1 and 12 weeks after therapy (POST). LV tissue obtained at POST was used to assess volume fraction of interstitial fibrosis (VFIF), SERCA-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, EDV and ESV increased and EF decreased significantly from PRE to POST (EF: 30±2 vs. 27±1 %, p<0.05). In CAP-treated dogs, EDV was unchanged; EF increased significantly after one week (36±2 vs. 27±2 %, p<0.05) with a further increase at POST (39±2 %, p<0.05) while ESV decreased. CAP significantly decreased VFIF, normalized SERCA-2a activity and expression of UCP-2 and -3, and GLUT-1 and -2 and significantly decreased NE and nt-pro BNP. Conclusion In HF dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial AD A1R agonists for the treatment of chronic HF.

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4 The Adenosine A1 Receptor and its Ligands

Cited by 23 publications

References 134 publications

Partial adenosine A1 receptor agonists for cardiovascular therapies

Partial adenosine A1 receptor agonists for cardiovascular therapies

Current and future G protein-coupled receptor signaling targets for heart failure therapy

Chronic Therapy With a Partial Adenosine A1-Receptor Agonist Improves Left Ventricular Function and Remodeling in Dogs With Advanced Heart Failure

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