Structural Simplification from Tricyclic to Bicyclic Scaffolds: A Long-Term Investigation in the Field of Adenosine Receptor Antagonists

Adenosine receptor (AR) antagonists have attracted considerable interest due to their therapeutic potential in a wide range of pathological conditions, including neurological, cardiovascular, and inflammatory disorders. Although a large number of AR antagonists have been developed worldwide, the interest in new derivatives remains high, and achieving subtype selectivity continue to be a major challenge. This review summarizes our research on adenosine receptor antagonists, highlighting the discovery of potent and selective compounds for the diverse AR subtypes across various chemical classes. Specifically, the paper focuses on the study of the triazolo[4,3-a]quinoxalin-1-one (<b>TQX</b>) and pyrazolo[3,4-c]quinoline (<b>PQ</b>) series, along with their simplified analogues, which have yielded highly potent and selective AR antagonists. An overview of the structure-activity relationship (SAR) studies and molecular docking investigations is provided, emphasizing the structural requirements for A_2A and A₃ receptor-ligand interaction. In addition, we present pharmacological studies of selected AR antagonists, in various in vitro and in vivo models of pain, depression, neuroinflammation-related diseases, and cancer.