A2B Receptor Ligands: Past, Present and Future Trends

G.      Ortore; A.      Martinelli

Abstract

A2B 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, Ca2+ 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 A2B 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 A2B 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 A2B antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: Ki(A2B)=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldis group: Ki(A2B)=5.5 nM, selectivity > 180 fold), LAS38096 (Almirall Prodesfarma: Ki(A2B)=17 nM, selectivity > 60 fold), OSIP339391 (OSI Pharmaceuticals: Ki(A2B)=0.5 nM, selectivity > 80 fold), PSB601 (Bonn University: Ki(A2B)=3.6 nM, selectivity > 140 fold) and the deazaxanthine 32 of Carottis group (Ki(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 A2B agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.

Keywords: A2B, A2B antagonist, A2B agonist, A2B receptor, CVT-6883, MRE-2029-F20, LAS38096, OSIP339391, PSB601, BAY-60-6583, Asthma, inflammation, angiogenic diseases, atherosclerosis, cardioprotection, tumor