ChemInform Abstract: A Functional Screening of Adenosine Analogues at the Adenosine A<sub>2B</sub> Receptor: A Search for Potent Agonists.

Zwart, M. De; Link, Regina; Kuenzel, J. K. Von Frijtag Drabbe; Cristalli, Gloria; Jacobson, Kenneth A.; Townsend‐Nicholson, Andrea; Ijzerman, A. P.

doi:10.1002/chin.199837252

Cited by 4 publications

(5 citation statements)

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“…We indeed confirmed that prediction using the highly selective A 2b AR agonist BAY 60-6583 [14]. 5′-( N -ethylcarboxamido) adenosine (NECA) is a potent, although not selective, A 2b AR agonist with an EC 50 for raising cAMP in cells expressing A 2b AR of ~3.1 μM [4]. NECA at reperfusion is as protective as AMP579, and the protection is dependent on the involvement of A 2b receptors [23].…”

Section: Introductionsupporting

confidence: 76%

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AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

Liu

Yang

et al. 2009

Basic Res Cardiol

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The mixed A 1 /A 2a -adenosine agonist AMP579 given at reperfusion is protective in animal models of myocardial infarction. Receptor-blocking studies have indicated that the protection came from an adenosine receptor (AR), but neither A 1 -nor A 2a -selective agonists could duplicate its protection. We recently found that A 2b -selective agonists given at reperfusion are protective, and, therefore, tested whether AMP579 might also be an A 2b agonist. We used human embryonic kidney cells overexpressing human A 2b receptors as an assay system. In these cells, A 2b receptor occupancy causes phosphorylation of ERK. AMP579 induced ERK phosphorylation with an EC 50 of 250 nM and this phosphorylation could be blocked by MRS1754 or PSB1115, two highly selective blockers of human A 2b receptors. We attempted to confirm our A 2b hypothesis in a rabbit heart model of ischemia-reperfusion. AMP579 (500 nM) for 1 h starting at reperfusion reduced infarct size in isolated rabbit hearts exposed to 30 min of regional ischemia and 2 h of reperfusion (12.9 ± 2.2% infarction of risk zone vs. 32.0 ± 1.9% in untreated hearts). PSB1115 (500 nM) given for the first 15 min of reperfusion blocked AMP579's protection (32.2 ± 3.1% infarction) which is consistent with an A 2b mechanism. We conclude that AMP579 is a non-selective, but potent A 2b -AR agonist, and that its protection against infarction is through that receptor.

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Section: Introductionsupporting

confidence: 76%

“…They differ only by the side groups on the adenine moiety. It is noteworthy that AMP579 with an EC 50 of about 250 nM for the A 2b receptor is about 100 times more potent than NECA [4]. The highly A 2b -selective BAY 60–6583 is even more potent with an EC 50 of about 10 nM [14].…”

Section: Discussionmentioning

confidence: 99%

AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

Liu

Yang

et al. 2009

Basic Res Cardiol

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“…Substitution at C8 of the adenine ring of adenosine led to a decreased affinity for all adenosine receptors, presumably due to a conformational change of the nucleoside from an anti -conformation to a less favorable syn -conformation. The presence of nitrogen at the 3 and 7 positions is important for activity with all receptor subtypes. , A number of SAR studies have revealed that modifications at C2 and N6 of the adenine can be tolerated. Agonist 5 , a C2 aniline derivative briefly discussed in the historical agonists section of this review, displays 10-fold selectivity for A 2 versus A 1 and as such was the first reported A 2 selective agonist .…”

Section: Therapeutic Applications Of A2a Receptor Agonistsmentioning

confidence: 99%

Adenosine A_2A Receptor as a Drug Discovery Target

2013

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The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.

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“…The first potent adenosine-like ligand, 5 -N-carboxamido adenosine (NECA, 50) was identified thanks to the development of a functional screening, based on adenylate cyclase stimulation [71]. Using this scaffold, several derivatives were synthesized, by substitution at the N-6, C2-positions of the purine heterocycle and/or at the 5 -position of the ribose moiety, with the aim of identifying the structural basis of the A 2B affinity and selectivity.…”

Section: Adenosine-likementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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A(2B) adenosine receptors have been investigated in recent years as potential target for the treatment of different pathologies. The involvement of this receptor in processes such as interleukins secretion, Ca(2+) mobilization, hepatic glucose regulation, tumor vascularisation, and cardioprotection have stimulated many researchers to develop specific agonists and antagonists. For many years, the lack of potent and selective A(2B) ligands precluded a deep exploration of their therapeutic prospective; at present, much progress in the field of antagonists led to preclinical studies for different compounds. Less populated is the universe of A(2B) agonists, but really promising for the involvement in ischemic preconditioning. A summary of the most significant advancements in the synthesis of new compounds and of the principal structure activity relationships is reported. The xanthine-based A(2B) antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: K(i(A2B))=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldi's group: K(i(A2B))=5.5 nM, selectivity >180 fold), LAS38096 (Almirall Prodesfarma: K(i(A2B))=17 nM, selectivity >60 fold), OSIP339391 (OSI Pharmaceuticals: K(i(A2B))=0.5 nM, selectivity >80 fold), PSB601 (Bonn University: K(i(A2B))=3.6 nM, selectivity >140 fold) and the deazaxanthine 32 of Carotti's group (K(i(A2B))=11 nM, selectivity >90 fold). Other recently emerging scaffolds with promising biological profiles are described. With regard to the agonists, many research groups are involved in the discovery of useful agonist radioligands, but the only example of potent and rather selective A(2B) agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.

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ChemInform Abstract: A Functional Screening of Adenosine Analogues at the Adenosine A_2B Receptor: A Search for Potent Agonists.

Cited by 4 publications

References 1 publication

AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

Adenosine A_2A Receptor as a Drug Discovery Target

A2B Receptor Ligands: Past, Present and Future Trends

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ChemInform Abstract: A Functional Screening of Adenosine Analogues at the Adenosine A2B Receptor: A Search for Potent Agonists.

Cited by 4 publications

References 1 publication

AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

AMP579 is revealed to be a potent A2b-adenosine receptor agonist in human 293 cells and rabbit hearts

Adenosine A2A Receptor as a Drug Discovery Target

A2B Receptor Ligands: Past, Present and Future Trends

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Product

Resources

About

ChemInform Abstract: A Functional Screening of Adenosine Analogues at the Adenosine A_2B Receptor: A Search for Potent Agonists.

Adenosine A_2A Receptor as a Drug Discovery Target