Editorial [Hot Topic: The Adenosinergic System - From Physiology to Pathology and Therapeutics (Guest Editors: A. Rees and J. Ham)]

Adenosine is universally expressed in all cells. Adenosine is continually formed and destroyed during general cell metabolism by a series of dephosphorylation steps mediated by specific nucleotidases. Within the cell, adenosine levels are usually low but during times of cellular activity or stress (such as hypoxia, inflammation etc), levels rise markedly as a result of increased enzymatic activity. The net effect under pathological conditions is an accumulation of adenosine outside of the cell. Extracellular adenosine can activate at least four receptors: A1, A2a, A2b and A3; these receptors have vastly different affinities for adenosine and different signal transduction properties. These properties allow adenosine receptors to mediate a wide variety of actions that may also be cell specific; these include neuronal transmission, vasodilatation, growth control and macrophage activation. Adenosine, in clinical terms, is perhaps most recognised for its role in cardiac blood flow and heart arrhythmias and this area of research has been extensively studied. The aims of the theme “The adenosinergic system - from physiology to pathology and therapeutics” in this edition of Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry are to describe some of the less well-known diseases where adenosine action may be implicated. As adenosine accumulates during cellular stress it is entirely reasonable to suggest that it could have a functional role in inflammatory situations such as rheumatoid arthritis, wound healing and respiratory disease. Similarly, adenosine accumulates in hypoxia and could have a role in cancer, particularly in the larger tumours where it is a contributing factor in growth control. Its role as a neurotransmitter is clear but data are emerging on its potential value in neuroprotection and disease control in neurodegenerative conditions such as Parkinson's disease and Huntington's disease. A completely new area of investigation is how adenosine may affect the differentiation and function of bone (osteoblast) cells. The article on animal models, including “knockout animals” (null animals for all four receptors have now been created) is particularly pertinent in trying to understand the precise roles of each of the receptors. The authors, recognised experts in their field, have been asked, not only to describe the role of adenosine in a particular setting or disease but also to consider the clinical aspects in terms of drug treatment and development. In support of this there are a number of companies who have a commercial interest in adenosine and several compounds are now in phase 1 and 2 clinical trials.