Pharmacological Insights into Safety and Efficacy Determinants for the Development of Adenosine Receptor Biased Agonists in the Treatment of Heart Failure

Patricia Rueda, Jon Merlin, Stefano Chimenti, Michel Feletou, Jerome Paysant, Paul J. White, Arthur Christopoulos, Patrick M. Sexton, Roger J. Summers, William N. Charman, Lauren T. May, Christopher J. Langmead

Preprint posted on July 23, 2020

Article now published in Frontiers in Pharmacology at

My heart will go on: researchers characterise the pharmacology of the adenosine receptor amidst heart failure drug discovery efforts

Selected by Zhang-He Goh

Background of preprint: the spaces between ARs

Adenosine receptors (ARs) are key mediators in cardiovascular function. They control heart rate and conduction [1,2], autonomic control and vasoregulation [3,4], perfusion, and growth and remodelling. Their agonism can offer protection from injury [5]: A1R agonists reduce the neurohormonal [6] and inflammation [7,8] responses [9-11]; while A2BR agonists promote cardiac fibroblast proliferation and collagen synthesis [12-16].

The strategy of targeting ARs to mitigate heart failure is currently complicated by ARs’ systemic expression and their multiple roles in the modulation of other cardiac [3,4] and renal [17,18] processes. Despite these difficulties, some selectivity has since been achieved by exploiting ARs’ ability to exhibit biased agonism with VCP746 and its analogues [19,20]. In fact, Bayer’s capadenoson [21,22] and neladenoson [23-27] progressed into preclinical models and clinical trials, suggesting that such a strategy may indeed be viable. Therefore, to enhance our understanding of these characteristics, Rueda et al. characterised and compared the preclinical pharmacology of VCP746, capadenoson, neladenoson, and the pan-AR agonist NECA (Fig. 1).

Figure 1. Agonists investigated by Rueda et al. in their preprint.

Key findings of preprint: opening the door to the heart

Rueda et al. first characterised the differential activity of VCP746, neladenoson, and capadenoson at A1 and A2B receptors, comparing their pharmacological profiles to the full agonist NECA. They made several key findings (Table 1):

  • VCP746 exhibited a high potency at A2BR, weak activity at A2AR, and minimal activity at A3R
  • Capadenoson’s selectivity for ARs ran in the following descending order: A1R > A2BR > A2AR >> A3R
  • Neladenoson was active at A2BR, but did not exhibit appreciable activity at A2AR or A3R
  • Neladenoson was a selective A1R biased agonist, with biased, weak agonism at the A2BR subtype
  • VCP746 was a biased A1R agonist and potent unbiased agonist at A2B

Rueda et al. then assessed the physiological effects of VCP746 and neladenoson. The authors first found that these two agents are anti-hypertrophic in cardiomyoctes—an effect associated with A1R inhibition [9], though these inhibitory effects were not caused by a reduction in cell viability. VCP746 and neladenoson were also anti-fibrotic in cardiac fibroblasts via their A2BR agonism.

Next, the authors characterised the in vitro, ex vivo, and in vivo effects of VCP746 and neladonoson on heart rate. In primary rat neonatal ventricular cardiomyocytes (NVCM), neladoson, but not VCP746, induced a slow heart rate through A1R-agonist-induced negative chronotropy. In ex vivo rat-isolated right atria, both neladenoson and VCP746 had minimal effects when compared to NECA. In vivo, neladenoson decreased heart rate in rats, while VCP746 increased it.

Table 1. Activities of VCP746, neladenoson, and capadenoson at various ARs.

Because renal disease often manifests in patients with heart failure, Rueda et al. next investigated the roles that ARs play in renal haemodynamics. The authors showed that A2B­R-mediated vasodilation could be induced by VCP746 and neladenoson, but not A1R-mediated vasoconstriction; they ascribed the latter finding to the biased agonism of VCP746 and neladenoson. In the same vein (pun intended), the authors found that VCP746 and neladenoson also did not induce A2AR-mediated rat thoracic aorta relaxation in vivo.

What I like about this preprint: ARs—a lifetime of research

I picked this preprint because it answers an interesting research question. As Rueda et al. point out, pharmacologists have been targeting ARs (especially A1R) for over two decades. Yet, efforts in creating a selective A1R agonist have been stymied by adverse effects arising from the difficulty of selective A1R agonism—the widespread distribution of A1R and its myriad physiological effects make such approaches too risky. Two main strategies have since been developed to target this problem: partial agonism, as seen in Bayer’s capadenoson and neladenoson; and biased A1R agonism, which elicit different effects despite targeting A1R.

In their preprint, Rueda et al. seek to clarify the pharmacology of targeting ARs. The authors’ in vitro, ex vivo, and in vivo work suggests that AR full and partial agonists indeed exhibit different pharmacodynamics and elicit different pharmacological responses at different sites. The authors’ findings gathered from a range of laboratory models allowed them to compare these differential pharmacological responses (Table 1). These findings in turn may shed some light on the finding that capadenoson and neladenoson did not appear to affect heart rate in clinical trials [25,26].

Future work: research into ARs and the heart will go on and on

Given the vast complexity in AR pharmacology, future work will be necessary to better understand the pharmacology of A1R agonism. A few key questions remain.

The authors, for one, ask whether A1R agonists with a cAMP-calcium bias but without the bias away from cAMP signalling is possible. A medicinal chemistry campaign involving the development of a structural understanding and the generation of the structure-activity relationship will be needed to answer this question.

Moreover, the lack of clinical translation should also be taken into consideration vis-à-vis­ the authors’ findings in various models. Traditionally, preclinical models involve the use of rodents (e.g. mice and rats) and non-rodents (e.g. dogs and monkeys) in testing, in addition to various in vitro tests. But to what extent do these reflect the pharmacodynamics of these agents in the human body?

One last major consideration involves the pharmacokinetics of potential AR agonists. Even if a selective and biased A1R agonist can be developed, what will the pharmacokinetic (PK)-pharmacodynamic (PD) relationship be? The multitude of factors at play, such as the partial agonist properties of these agents, may further complicate the PK-PD relationship. This in turn may have implications for clinical dosing.

All in all, the findings by Rueda et al. point to the difficulties in manipulating AR pharmacology. Until the roles of AR in cardiac function are more clearly identified, research into the relationship between AR agonism and its cardiac effects will go on.

Open questions

  1. It is interesting that selective A1R targeting can have so many physiological effects, giving rise to the phenomenon of partial agonism. Has the molecular basis for this phenomenon been established? How do you think this will be further developed moving forward?


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Tags: adenosine, cardiac fibroblast, inflammation

Posted on: 8th September 2020


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