Once Upon a Time Adenosine and Its Receptors: Historical Survey and Perspectives as Potential Targets for Therapy in Human Diseases

Endogenous autacoid adenosine plays important physiological roles in various tissues and organs by acting through A1, A2A, A2B, and A3 receptors. Dysregulated extracellular adenosine concentrations can cause many disorders such as in!ammation, neurodegeneration, pain, and cancer, thus suggesting adenosine receptors (ARs) as interesting therapeutic targets. Medicinal chemistry studies have generated a large number of AR ligands, which have been pharmacologically characterized and optimized. Improvement in AR structural biology stimulated new computer-aided drug design approaches for drug discovery. Some AR ligands have reached clinical trials, and a limited number of them are on the market. To achieve these results, great progress has been made since the first steps in the intriguing world of adenosine and its receptors. New knowledge has been achieved, many issues have been solved, and new important aspects, previously ignored or underestimated, have been highlighted. In particular, but not only, taking into account important factors such as binding kinetics and biased signaling of ARs can lead to a rational design of more effective and safer drugs. Multitarget-directed ligands that combine, in the same molecule, the ability to interact with AR(s) and other target(s) are getting much attention as innovative therapeutic agents for treating multifactorial disorders such as neurodegenerative diseases and cancer.