Neladenoson Bialanate Hydrochloride: A Prodrug of a Partial Adenosine A<sub>1</sub> Receptor Agonist for the Chronic Treatment of Heart Diseases

Meibom, Daniel; Albrecht-Küpper, Barbara; Diedrichs, Nicole; Hübsch, Walter; Kast, Raimund; Krämer, Thomas; Krenz, Ursula; Lerchen, Hans‐Georg; Mittendorf, Joachim; Nell, Peter G.; Süssmeier, Frank; Vakalopoulos, Alexandros; Zimmermann, Katja

doi:10.1002/cmdc.201700151

Cited by 48 publications

(41 citation statements)

References 27 publications

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“…In the case of the adenosine A 1 ‐receptor, a number of compounds have previously undergone evaluation for cardiovascular disease indications such as paroxysmal supraventricular tachycardia, atrial fibrillation, and angina pectoris (Müller & Jacobson, ). At the present time, the A 1 ‐receptor partial agonist neladenoson is undergoing clinical trial for heart failure (Meibom et al, ). However, the ubiquitous distribution of adenosine receptors in the body can often limit therapeutic application because of the effects of adenosine ligands on the same receptor in a different tissue or cell type (Müller & Jacobson, ).…”

Section: Introductionmentioning

confidence: 99%

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Cooper

Soave

Jörg

et al. 2019

British J Pharmacology

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Background and Purpose Adenosine is a local mediator that regulates a number of physiological and pathological processes via activation of adenosine A1‐receptors. The activity of adenosine can be regulated at the level of its target receptor via drugs that bind to an allosteric site on the A1‐receptor. Here, we have investigated the species and probe dependence of two allosteric modulators on the binding characteristics of fluorescent and nonfluorescent A1‐receptor agonists. Experimental Approach A Nano‐luciferase (Nluc) BRET (NanoBRET) methodology was used. This used N‐terminal Nluc‐tagged A1‐receptors expressed in HEK293T cells in conjunction with both fluorescent A1‐receptor agonists (adenosine and NECA analogues) and a fluorescent antagonist CA200645. Key Results PD 81,723 and VCP171 elicited positive allosteric effects on the binding affinity of orthosteric agonists at both the rat and human A1‐receptors that showed clear probe dependence. Thus, the allosteric effect on the highly selective partial agonist capadenoson was much less marked than for the full agonists NECA, adenosine, and CCPA in both species. VCP171 and, to a lesser extent, PD 81,723, also increased the specific binding of three fluorescent A1‐receptor agonists in a species‐dependent manner that involved increases in Bmax and pKD. Conclusions and Implications These results demonstrate the power of the NanoBRET ligand‐binding approach to study the effect of allosteric ligands on the binding of fluorescent agonists to the adenosine A1‐receptor in intact living cells. Furthermore, our studies suggest that VCP171 and PD 81,723 may switch a proportion of A1‐receptors to an active agonist conformation (R*).

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Section: Introductionmentioning

confidence: 99%

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Cooper

Soave

Jörg

et al. 2019

British J Pharmacology

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“…Structural modifications at the exocyclic amine group of Capadenoson led to the development of the A 1 AR agonist 2-(((2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl)sulfanyl)-4-(4-(2-hydroxyethoxy) phenyl)-6-(pyrrolidin-l-yl)pyridine-3,5-dicarbonitrile, also named Neladenoson (2; Figure 1; Table 1). Like Capadenoson, Neladenoson is a selective partial agonists of the A 1 AR [50,51]. Neladenoson showed cardioprotective effects in rat preclinical models, analogously to Capadenoson, although with lower central effects.…”

Section: Pyridine Derivativesmentioning

confidence: 99%

Non-Nucleoside Agonists of the Adenosine Receptors: An Overview

et al. 2019

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Potent and selective adenosine receptor (AR) agonists are of pharmacological interest for the treatment of a wide range of diseases and conditions. Among these derivatives, nucleoside-based agonists represent the great majority of molecules developed and reported to date. However, the limited availability of compounds selective for a specific AR subtype (i.e., A2BAR) and a generally long and complex synthetic route for largely substituted nucleosides are the main drawbacks of this category of molecules. Non-nucleoside agonists represent an alternative set of compounds able to stimulate the AR function and based on simplified structures. This review provides an updated overview on the structural classes of non-nucleoside AR agonists and their biological activities, with emphasis on the main derivatives reported in the literature. A focus is also given to the synthetic routes employed to develop these derivatives and on molecular modeling studies simulating their interaction with ARs.

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“…The growing interest in this class is also dictated by the fact that non-nucleoside AR agonists seem to be more versatile for pharmacological studies, showing fewer species differences than the adenosine-like ones [4]. Moreover, the studies carried out to date are sufficient to underline the versatility of the amino-3,5-dicyanopyridine scaffold for producing AR ligands with not only a wide range of affinities but, interestingly, with different degrees of efficacy at the different ARs [11,12,[14][15][16][17][18][19].…”

Section: Chemistrymentioning

confidence: 99%

“…All the derivatives that interact with the hA 2B AR (2, 3, 5-8, 10-12) display EC 50 values from 12 to 260 nM behaving as partial agonists, with the only exception being compound 6, previously reported as trifluoroacetate salt [32], which shows a full agonist profile. Some compounds (17)(18)(19)(20), selected among those that had no activity at the hA 2B AR were also evaluated to investigate their antagonistic effect on cAMP production stimulated by 5 -(N-ethylcarboxamido)adenosine (NECA) 100 nM in hA 2B CHO cells. These functional studies reveal their inability to inhibit NECA-stimulated cAMP levels (I% ≤ 3) (data not shown).…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors. Ranging from Pan Ligands to Combined A1/A2B Partial Agonists

et al. 2019

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The amino-3,5-dicyanopyridine derivatives belong to an intriguing series of adenosine receptor (AR) ligands that has been developed by both academic researchers and industry. Indeed, the studies carried out to date underline the versatility of the dicyanopyridine scaffold to obtain AR ligands with not only a wide range of affinities but also with diverse degrees of efficacies at the different ARs. These observations prompted us to investigate on the structure–activity relationships (SARs) of this series leading to important previously reported results. The present SAR study has helped to confirm the 1H-imidazol-2-yl group at R2 position as an important feature for producing potent AR agonists. Moreover, the nature of the R1 substituent highly affects not only affinity/activity at the hA1 and hA2B ARs but also selectivity versus the other subtypes. Potent hA1 and hA2B AR ligands were developed, and among them, the 2-amino-6-[(1H-imidazol-2-ylmethyl)sulfanyl]-4-[4-(prop-2-en-1-yloxy)phenyl]pyridine-3,5-dicarbonitrile (3) is active in the low nanomolar range at these subtypes and shows a good trend of selectivity versus both the hA2A and hA3 ARs. This combined hA1/hA2B partial agonist activity leads to a synergistic effect on glucose homeostasis and could potentially be beneficial in treating diabetes and related complications.

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

Cited by 48 publications

References 27 publications

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Non-Nucleoside Agonists of the Adenosine Receptors: An Overview

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors. Ranging from Pan Ligands to Combined A1/A2B Partial Agonists

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

Cited by 48 publications

References 27 publications

Probe dependence of allosteric enhancers on the binding affinity of adenosine A1‐receptor agonists at rat and human A1‐receptors measured using NanoBRET

Probe dependence of allosteric enhancers on the binding affinity of adenosine A1‐receptor agonists at rat and human A1‐receptors measured using NanoBRET

Non-Nucleoside Agonists of the Adenosine Receptors: An Overview

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors. Ranging from Pan Ligands to Combined A1/A2B Partial Agonists

Contact Info

Product

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

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET

Probe dependence of allosteric enhancers on the binding affinity of adenosine A₁‐receptor agonists at rat and human A₁‐receptors measured using NanoBRET