Biochemical and Pharmacological Role of A1 Adenosine Receptors and Their Modulation as Novel Therapeutic Strategy

Adenosine, the purine nucleoside, mediates its effects through activation of four G-protein coupled adenosine receptors (ARs) named as A(1), A(2A), A(2B) and A(3). In particular, A(1)ARs are distributed through the body, primarily inhibitory in the regulation of adenylyl cyclase activity and able to reduce the cyclic AMP levels. Considerable advances have been made in the pharmacological and molecular characterization of A(1)ARs, which had been proposed as targets for the discovery and drug design of antagonists, agonists and allosteric enhancers. Several lines of evidence indicate that adenosine interacting with A(1)ARs may be an endogenous protective agent in the human body since it prevents the damage caused by various pathological conditions, such as in ischemia/hypoxia, epileptic seizures, excitotoxic neuronal injury and cardiac arrhythmias in cardiovascular system. It has also been reported that one of the most promising targets for the development of new anxiolytic drugs could be A(1)ARs, and that their activation may reduce pain signaling in the spinal cord. A(1)AR antagonists induce diuresis and natriuresis in various experimental models, mediating the inhibition of A(1)ARs in the proximal tubule which is primarily responsible for reabsorption and fluid uptake. In addition, the results of various studies indicate that adenosine is present within pancreatic islets and is implicated through A(1)ARs in the regulation of insulin secretion and in glucose concentrations. In the present paper it will become apparent that A(1)ARs could be implicated in the pharmacological treatment of several pathologies with an important influence on human health.