Adenosine Receptor Antagonists:  Translating Medicinal Chemistry and Pharmacology into Clinical Utility

The first recorded report describing evidence for an AR originates from 1976. Now, 30 years later, advances in understanding the role of adenosine and its receptors in physiology and pathophysiology as well as new developments in medicinal chemistry of these receptors have enabled researchers to identify potential therapeutic areas for drug development. With the combination of pharmacological data, using selective ligands and genetically modified mice, important progress has been made toward an understanding of the role of ARs in a variety of diseases, such as inflammatory conditions, sepsis, heart attack, ischemia-reperfusion injury, vascular injury, spinal cord injury, chronic obstructive pulmonary disease (COPD), asthma, diabetes, obesity, inflammatory bowel disease, retinopathy, and Parkinson’s Disease (PD). Nonselective AR antagonists are used to maintain wakefulness (caffeine) and, less commonly at present, treat bronchospasm (theophylline, aminophylline, enprofylline). Currently a number of new selective AR agonists and antagonists are in testing for a variety of new indications. Therefore, the purpose of this review is to analyze the structure-activity relationships of the ligands synthesized as antagonists for the ARs. We have included some synthetic schemes in order to show the chemistry involved in this field. In particular, we will investigate antagonists under active development that selectively target the four known AR subtypes.