Invited Lectures

Abstract

Following a brief account of the early history of the discovery of purinergic signalling, a personal view of some of the exciting cutting-edge directions being taken by research in the field will be considered. In particular, emphasis will be placed on the pathophysiology of purinergic signalling and its therapeutic potential.Recent advances in understanding the role of adenosine and its receptors in physiology and pathophysiology as well as new developments in medicinal chemistry of these receptors have made it possible to begin to realize the therapeutic potential of adenosine and its receptors. Currently adenosine itself is targeted at the heart; a bolus of adenosine intravenously is commonly used to treat supraventricular tachycardia whereas an infusion of adenosine is used as a coronary vasodilator during pharmacologic stress testing. Non-selective adenosine receptor antagonists are used to maintain wakefulness (caffeine), as an analgesic (caffeine) and, less commonly at present, to treat bronchospasm (theophylline, aminophylline, enprofylline). Currently a number of new selective adenosine receptor agonists and antagonists are in testing for a variety of new indications and one adenosinetargeted indication. The older indication is pharmacologic stress testing and new selective A 2A receptor agonists, ATL146e (Apadenoson, Adenosine Therapeutics) and Regadenoson (CV Therapeutics), are currently under study (Phase II-III) for this indication. In addition, a selective A 1 receptor agonist is in trials for supraventricular tachycardia (tecadenoson, CV Therapeutics), Currently a number of companies are testing selective adenosine receptor agonists for newer indications including Rheumatoid Arthritis, cancer and wound healing, Adenosine A 3 receptor agonists are in trials for the treatment of Rheumatoid Arthritis and Cancer (CF101, CF102, Can-Fite Biopharmaceuticals) and preliminary promising results in patients with RA have been reported. Topical application of an adenosine A 2A receptor agonist to promote healing of diabetic foot ulcers is currently in Phase II trials after the successful completion of a Phase I safety/early efficacy trial (MRE94, King Pharmaceuticals). An allosteric enhancer at the adenosine A 1 receptor is in trials for neuropathic pain (T-62, King Pharmaceuticals). Because adenosine receptor stimulation may also be involved in disease pathogenesis selective adenosine receptor antagonists are being studied for select indications as well. Istradefylline (KW-6002, Kyowa Pharmaceuticals), a selective adenosine A 2A receptor antagonist, is now in late stage clinical trials for the treatment of Parkinson"s Disease. Another approach to targeting adenosine receptors is to increase extracellular adenosine concentrations, mechanisms shown to mediate the anti-inflammatory effects of two drugs commonly used in the treatment of Rheumatoid Arthritis, methotrexate and sulfasalazine. Dipyridamole inhibits adenosine uptake and this clearly underlies its effect as a coronary vasodilator during pharmacologic ca...