A2B Receptor Ligands: Past, Present and Future Trends

Abstract

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.

Modulation of A1 and A2B adenosine receptor activity: a new strategy to sensitise glioblastoma stem cells to chemotherapy

“… 38 As shown in Figure 1d , treatment with CHA and BAY606583 increased the level of GTP γ S binding in a concentration-dependent manner, yielding EC 50 values of 6.1±0.5 and 1.9±0.2 nM, respectively; these values are comparable to their affinity constant values vis a vis A 1 AR and A 2B AR. 39 , 40 In a similar manner, CGS21680 and Cl-IBMECA stimulated GTP γ S binding, yielding affinity constant values of 41.9±4.5 and 0.46±0.06 nM, respectively, consistent with those previously reported. 41 , 42 …”

Highly selective A1‐adenosine‐agonist (2‐chloro‐N6‐cyclopentyladenosine) and reduction of flap necrosis in adipocutaneous flaps in rats

“…In addition, activation of A 2a receptors lead to a blocking of neutrophile granulocytes in producing superoxide radicals, their degranulation or adhesion at endothelium and to attenuation of inflammatory and immune factors 33. A 2b adenosine receptors have been investigated in recent years as a potential target for the treatment of different diseases 34. The involvement of this receptor in processes such as interleukins secretion, Ca 2+ ‐mobilization, hepatic glucose regulation, tumor vascularization, and cardioprotection was proved.…”

Recent developments in adenosine receptor ligands and their potential as novel drugs

“…The SAR of adenosine agonists at the A 2B AR was recently reviewed [11,13]. Substitution of adenosine at the N 6 -position with a narrow range of aryl groups increases affinity at the A 2B AR.…”

“…A 2B AR antagonists have recently been reviewed [12,13]. Certain modifications of the xanthine core structure at the 8-position with aryl groups have been found to result in selectivity for the A 2B AR [15].…”

“…1–9 and Tables 1–3). The most recent class of selective AR ligands to be reported is the class of A 2B AR agonists [11–13]. The availability of these selective ligands has facilitated research on therapeutic applications of modulating the ARs and in some cases has provided clinical candidates.…”