It is well known that adenosine is an important intermediary metabolite, acting as a building block for nucleic acids and a component of the biological energy currency ATP. In addition, adenosine functions as a signalling molecule through the activation of four distinct adenosine receptors-denoted A1, A2A, A2B and A3. These receptors are widely expressed and have been implicated in several biological functions, both physiological and pathological. These include cardiac rhythm and circulation, lipolysis, renal blood flow, immune function, sleep regulation and angiogenesis, as well as inflammatory diseases, ischaemia-reperfusion and neurodegenerative disorders.
Adenosine is a small molecule that is found throughout the body and is structurally and metabolically related to ATP. Nearly all mammalian organ systems are affected by adenosine. Adenosine can transport in and out of cells by a diffusive mechanism. Adenosine typically acts locally in the body due to a short half life (seconds). Many cells can make their own adenosine, which is also a by-product of ATP metabolism. Adenosine plays a key role in energy supply and demand. As ATP is a primary source of energy, an excess of adenosine can be a signal that high amounts of energy are being consumed triggering a depressant action in the cell. Caffeine is structurally similar to adenosine and acts as an antagonist for the adenosine receptors, essentially blocking this depressant action and the ability to regulate feedback control, resulting in the well-known stimulatory effects of caffeine.
Four adenosine receptor subtypes have been identified (A1, A2a, A2b, A3) and have been classified based on tissue distribution, effector system, and ligand specificity. A2a is of particular interest and was the focus of the majority of this thesis. A large effort has been undertaken to design ligands that are specific to a particular adenosine subtype. Structure activity relationships have been obtained via site-directed mutagenesis of specific amino acid residues, modeling, and the chemical synthesis of novel ligands. Adenosine receptors have long been sought as drug targets with the first report of potential actions of adenosine on the heart and blood vessels in 1929, but the short half life of adenosine caused interest to wane. The wide tissue distribution and the presence of numerous subtypes requires drug candidates to be highly selective. Drugs acting at adenosine receptors have potential therapeutic applications as cardioprotective agents, neuroprotective agents, sedatives, antipsychotics, stimulants, and antidepressants. More generally heart disease, Alzheimer's disease, Parkinson's disease, and cancer are all conditions that have been linked to possible therapeutic action via adenosine receptors.
Adenosine and its receptors have been implicated in a wide range of biological events. Adenosine receptors or receptor-mediated effects have been demonstrated in virtually every tissue or organ examined. Some of the most prominent physiologic or pharmacologic effects mediated by adenosine receptors include neurotransmission (A1 and A2a receptors), modulation of cardiac conduction (A1Rs), coronary vasodilation (A2aRs), regulation, indirectly, of airway tone (A2bRs), inhibition of inflammation (A2aRs primarily), and promotion of angiogenesis and wound healing (A2aR). Because of these known effects, there have been some clinical applications for adenosine and its analogues and there is great potential for new therapies based on compounds that selectively target individual adenosine receptor subtypes. For example, intravenous preparations of adenosine have been licensed for clinical use for the treatment of supraventricular tachycardia and infusions of adenosine are also licensed for clinical use as a coronary vasodilator for pharmacologic stress testing. Synthetic selective agonists of A2aR are currently undergoing preclinical testing for the treatment of allergen-induced inflammation, ischemia-reperfusion injury, sepsis and some autoimmune diseases. Clinical studies are also currently underway to determine the utility of topical A2aR agonists in the therapy of diabetic foot ulcers.
Ronald Thomas Niebauer. ENGINEERING YEAST CELLS FOR OPTIMAL EXPRESSION OF THE HUMAN ADENOSINE (A2A) RECEPTOR