Adenosine uptake inhibitors

Abstract

Adenosine is a purine nucleoside and modulates a variety of physiological functions by interacting with cell-surface adenosine receptors. Under several adverse conditions, including ischemia, trauma, stress, seizures and inflammation, extracellular levels of adenosine are increased due to increased energy demands and ATP metabolism. Increased adenosine could protect against excessive cellular damage and organ dysfunction. Indeed, several protective effects of adenosine have been widely reported (e.g., amelioration of ischemic heart and brain injury, seizures and inflammation). However, the effects of adenosine itself are insufficient because extracellular adenosine is rapidly taken up into adjacent cells and subsequently metabolized. Adenosine uptake inhibitors (nucleoside transport inhibitors) could retard the disappearance of adenosine from the extracellular space by blocking adenosine uptake into cells. Therefore, it is expected that adenosine uptake inhibitors will have protective effects in various diseases, by elevating extracellular adenosine levels. Protective or ameliorating effects of adenosine uptake inhibitors in ischemic cardiac and cerebral injury, organ transplantation, seizures, thrombosis, insomnia, pain, and inflammatory diseases have been reported. Preclinical and clinical results indicate the possibility of therapeutic application of adenosine uptake inhibitors.