oa Editorial [Hot topic: Adenosine Receptor Ligands: Where Are We, and Where Are We Going? (Guest Editors: Tiziano Tuccinardi and Adriano Martinelli)]

Adenosine is an endogenous purine nucleoside distributed in several tissues in mammalian organisms where it plays a key role in a large variety of physiological processes. Under normal conditions, adenosine is formed intracellularly and extracellularly. The intracellular production of adenosine is mainly derived from the dephosphorylation of AMP via a cytosolic 5'-nucleotidase, whereas the extracellular production of adenosine is mainly derived from the action of ecto-5'-nucleotidases that mediate the dephosphorylation of AMP derived from the metabolism of extracellular adenine nucleotides Currently, four adenosine receptor subtypes (A1, A2A, A2B, and A3) have been cloned and characterized in several species including rat, mouse, and human. These receptors belong to the rhodopsin-like family of G-protein-coupled receptors (GPCRs), and are encoded by distinct genes. The stimulation of adenosine receptors activates several effector systems, such as the enzyme adenylyl cyclase. A1 and A3 subtypes mainly signal via Gi proteins mediating the inhibition of adenylyl cyclase, whereas the A2A andA2B subtypes mainly signal via the Gs proteins, causing the activation of adenylyl cyclase and thus stimulating the formation of cAMP. Moreover, adenosine can also modulate additional effector systems, including potassium or calcium channels and phospholipases. Several experiments have provided insights into the physiology and pathophysiology of the four adenosine receptor subtypes. The activation of A1AR may be useful in protecting the heart and other tissues from ischemia. A1AR selective antagonists have a therapeutic potential in the treatment of various forms of dementia, such as Alzheimer's disease and depression. Activation of A2AAR is potentially useful for the treatment of cardiovascular diseases, such as hypertension, ischemic cardiomyopathy, inflammation, and atherosclerosis. A2AAR antagonists have been proposed as novel therapeutics for neurodegenerative diseases such as Parkinson's disease and epilepsy disorder. A2BAR agonists are therapeutically promising for their involvement in ischemic preconditioning and A2BAR antagonists have been reported for their activity in asthma and colonic inflammation. Finally, the A3AR agonists have cardioprotective and cerebroprotective effects as well as cytostatic properties, whereas A3AR antagonists could be used as potential drugs for the treatment of asthma and inflammatory conditions. Due to all these possible therapeutical applications, efforts have been carried out by industries and academicians in obtaining selective agonists, antagonists and allosteric enhancers for these four receptor subtypes. As a result, more than 20 clinical trials are currently ongoing and on April 10, 2008, CV Therapeutics, Inc. received approval from the US Food and Drug Administration (FDA) for the use of Lexiscan® (regadenoson; CVT-3146) as a pharmacological stress agent in conjunction with radionuclide MPI. This event can be considered the end point of about thirty years of studies on adenosine receptor ligands but also a new starting point for increasing the interest surrounding adenosine ligands. Two consecutives issues of Current Topics in Medicinal Chemistry highlight the most important aspects of research relating to adenosine. In this issue, the first article by Trincavelli and co-workers introduces adenosine receptors, and summarize what we know and what we are learning about adenosine receptor structure, signalling and regulatory mechanisms. In the second article, Schenone and co-workers focus on the A1 adenosine receptor ligands together with their potential therapeutic application, pointing the attention on their chemical structures and SAR and also reporting new findings on preclinical or clinical trials of some important A1 receptor ligands synthesized in the past. Using the same plan, in the following two articles Manera and co-workers and Martinelli and co-workers analyze the A2A and A2B receptor ligands, respectively.