Therapeutic Potentials of A2B Adenosine Receptor Ligands: Current Status and Perspectives

Abstract

Background: Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belong to the superfamily of G-protein coupled receptors (GPCRs). More than 40% of modern medicines act through either activation or inhibition of signaling processes associated with GPCRs. In particular, A2B AR signaling pathways are implicated in asthma, inflammation, cancer, ischemic hyperfusion, diabetes mellitus, cardiovascular diseases, gastrointestinal disorders, and kidney disease. Methods: This article reviews different disease segments wherein A2B AR is implicated and discusses the potential role of subtype-selective A2B AR ligands in the management of such diseases or disorders. All the relevant publications on this topic are reviewed and presented scientifically. Results: This review provides an up-to-date highlight of the recent advances in the development of novel and selective A2B AR ligands and their therapeutic role in treating various disease conditions. A special focus has been given to the therapeutic potentials of selective A2B AR ligands in the management of airway inflammatory conditions and cancer. Conclusions: This systematic review demonstrates the current status and perspectives of A2B AR ligands as therapeutically useful agents that would assist medicinal chemists and pharmacologists in discovering novel and subtype-selective A2B AR ligands as potential drug candidates.

Allosterism vs. Orthosterism: Recent Findings and Future Perspectives on A2B AR Physio-Pathological Implications

“…Conversely, several highly potent and selective A 2B AR antagonists have been reported and some of these had entered in clinical trials in the past decades. CVT-6883 (2, Table 1, also known as GS-601), developed by Gilead along with various other compounds, such as, CGS15493 (3, Table 1, developed by Novartis), WO-00125210 (Bayer HealthCare Pharmaceuticals), IPDX (4, Table 1, Vanderbilt University), and ATL-907 (Adenosine Therapeutics) have entered phase I and II trials for the treatment of asthma (Chandrasekaran et al, 2019;Effendi et al, 2020). In addition, the dual A 2B /A 3 AR antagonist QAF-807 (5, Table 1, Novartis) had reached phase III clinical trial but it failed to attenuate PC20 AMP challenge as a marker of airway inflammation in mild asthmatic subjects (Wilson, 2008).…”

Exploiting the Indole Scaffold to Design Compounds Binding to Different Pharmacological Targets

“…Particularly, selective agonists of this receptor have been reported to reduce inflammation after ventilator-induced lung injury [111] and to modulate myocardial adaptation to ischemia [112]. Selective A 2B AR antagonists have been regarded as candidates for the treatment of cancer [113,114], colitis [115,116] and asthma [117][118][119].…”

Molecular Simulations and Drug Discovery of Adenosine Receptors

“…It could regulate many cellular responses, such as inhibition of Ca 2+ conductance and stimulation of phospholipase C, K + conductance, phosphoinositide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) [ 8 , 9 ] ( Table 1 ). The A 1 AR is thus considered as a potential drug target for treating myocardial ischemia [ 10 ], cardiovascular disorders [ 11 , 12 ], obesity [ 13 ] and cancers [ 14 , 15 ]. Particularly, one agonist and four antagonists of A 1 AR were approved in the market ( Table 1 ).…”