A new chemical tool (C0036E08) supports the role of adenosine A2B receptors in mediating human mast cell activation

Buceta, Montserrat; Domínguez, Eduardo; Castro, Marián; Brea, José; Álvarez, David; Barcala, J. Gonzlez; Valdés, Luís; Álvarez-Calderón, Pedro; Domı́nguez, Fernando; Vidal, Bernat; Dı́az, José Luis; Miralpeix, Montse; Beleta, Jörge; Cadavid, Marı́a Isabel; Loza, Marı́a Isabel

doi:10.1016/j.bcp.2008.07.011

Cited by 8 publications

(4 citation statements)

References 33 publications

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“…Further optimization led to 1,3-dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives [49], some of them showing excellent A 2B affinities, high selectivity over A 2A and A 3 , but low selectivity over A 1 ( Table 7). C0036E08 (30) [50], for example, showed a kA 2B of 3,5 nM and a ratio A 2A /A 2B = 1412, while the ratio A 1 /A 2B is about 10.…”

Section: Deaza Xanthinesmentioning

confidence: 97%

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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Section: Deaza Xanthinesmentioning

confidence: 97%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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“…It is worth mentioning that inflammatory cytokines have stimulated [ 62 , 63 , 64 , 65 ] cells to synthesize other inflammatory cytokines, namely, IL-1β, TNF-α, IL-6, IL-8, and chemokines. The anti-inflammatory cytokines are a series of immune-regulatory molecules [ 34 , 50 , 66 , 67 ] that control the pro-inflammatory cytokine response.…”

Section: Resultsmentioning

confidence: 99%

Pyrrole and Fused Pyrrole Compounds with Bioactivity against Inflammatory Mediators

et al. 2017

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A new series of pyrrolopyridines and pyrrolopyridopyrimidines have been synthesized from aminocyanopyrroles. The synthesized compounds have been characterized by FTIR, 1H-NMR and mass spectroscopy. The final compounds have been screened for in vitro pro-inflammatory cytokine inhibitory and in vivo anti-inflammatory activity. The biological results revealed that among all tested compounds some fused pyrroles, namely the pyrrolopyridines 3i and 3l, show promising activity. A docking study of the active synthesized molecules confirmed the biological results and revealed a new binding pose in the COX-2 binding site.

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“…It was reported that the main mechanism of adenosine-induced bronchoconstriction appears to involve the release of inflammatory mediators from mast cells via activation of the A2B receptor [35]. Incubation of IL-4 with hCBMCs resulted in the increased expression of A2B and reduced expression of A2A adenosine receptors on human mast cells, and subsequently augmented antiIgE-and calcium ionophore-induced mast cell degranulation [36].…”

Section: Ck-rmentioning

confidence: 98%

Self-Amplification Mechanisms of Mast Cell Activation: A New Look in Allergy

Zhang

Zeng³

et al. 2012

CMM

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Allergic diseases are major diseases involving approximately 22% of world population. In recent years, accumulated evidence suggests that apart from IgE, allergens may provoke immediate allergic reactions via other pathways such as IgG, toll like receptor (TLR) dependent ones. In addition, large numbers of low molecular weight molecules (LMWM) such as sphingosine-1-phosphate and iodinated contrast agents have been observed to cause allergy. Therefore, the current definition of allergy, a group of IgE mediated diseases appears difficult to cover all allergic reactions. Since even IgE dependent allergic reactions are carried out through activation of mast cells and basophils, and all allergens mentioned above can activate these cells, we hypothesize that allergic reactions are mast cell and basophil mediated inflammatory process as it is the activated mast cells and basophils that initiate the pathological process of the immediate allergic reactions, whereas IgE only serves as one of the activators of these cells.

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A new chemical tool (C0036E08) supports the role of adenosine A2B receptors in mediating human mast cell activation

Cited by 8 publications

References 33 publications

A2B Receptor Ligands: Past, Present and Future Trends

A2B Receptor Ligands: Past, Present and Future Trends

Pyrrole and Fused Pyrrole Compounds with Bioactivity against Inflammatory Mediators

Self-Amplification Mechanisms of Mast Cell Activation: A New Look in Allergy

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