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. This second issue begins with the article by Taliani and co-workers which summarizes the most recent developments made in the field of selective A3 receptor ligands, pointing the attention on their main chemical structural features and on the SARs, which determine ligand affinity and selectivity for the target subtype. La Motta and co-workers updates the literature on allosteric modulators that has appeared in the last few years, focusing the attention on medicinal chemistry, in terms of chemical structure and SARs. Botta and co-workers and Dal Ben and co-workers report a computational analysis in terms of receptor and ligand-based studies and in the last article, Giordano and co-workers highlight the mouse animal models that have been useful in designing new selective adenosine ligands as well as discuss the main adenosine receptor ligands in clinical trials. As guest editors, we would like to thank the contributing authors for their efforts and, on behalf of all co-authors, we would like to express gratitude to Dr Allen Reitz, Editor-in-Chief of Current Topics in Medicinal Chemistry.