Federico Da Settimo Passetti

Synthesis and biological evaluation on human glioblastoma cells of novel pyrazolo3,4-Dpyrimidine adenosine A3 receptor antagonists

Third joint Italian-German Purine Club meeting: “Purinergic receptors: new frontiers for novel therapies” Invited Lectures Abstracts Purinergic signalling: some exciting new directions Geoffrey Burnstock Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK Presenting author: g.burnstock@ucl.ac.uk After a brief initial description of some of the important steps in the establishment of purinergic signalling, the talk will focus on some of the exciting new directions in the field, particularly those relating to purinergic pathophysiology and potential therapeutic applications. There will be discussion of the long-term trophic effects of purines and pyrimidines in blood vessel remodelling in restenosis; plasticity of purinergic cotransmission of diseased urinary bladder; hypertensive rats; spermmotility in IVF; purinergic mechanosensory transduction in visceral pain and the role of spinal microglial purinoceptors in neuropathic pain; the potential for P2X7 receptor antagonists in osteoporosis and kidney failure and the growing literature about the roles of purinergic signalling of disorders of the central nervous system; the role of ATP in the treatment of cancer; transient trophic purinergic signalling in embryological development and in stem cell activities; and studies of the evolutionary origins of purinergic receptors will also be discussed. Finally, a novel hypothesis will be presented for the involvement of purinergic signalling in acupuncture. New frontiers for ligands of adenosine and P2Y receptors Kenneth A. Jacobson National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, 20902, USA Presenting author: kajacobs@helix.nih.gov Selective agonists and antagonists are now available for each of the four adenosine receptor (AR) subtypes, making possible research advances leading to the implementation of new therapeutic concepts. Development of selective P2Y receptor ligands is also underway and has been aided by computer modeling and in silico screening. Nevertheless, the field of purine and pyrimidine signaling has particular challenges for medicinal chemists and pharmacologists. The bioavailability and stability of polar, charged, or hydrolyzable compounds are often limited. Effective and selective inhibitors of nucleotidases are lacking. The interplay of chemically related signaling molecules, their metabolism and formation, and time-dependent signaling, in any given cell or tissue, is to be considered as a system rather than as isolated components. The relationship of disease treatment to Gprotein-dependent and independent pathways needs to be established, and new assays are needed. The definition of agonism vs partial agonism vs antagonism may depend on the model used. Large species differences, affecting both affinity and efficacy of new compounds, exist for these receptors. Novel drug delivery or prodrug approaches are needed to overcome side effects because receptors tend to be widespread. In addition, the effects of oligomerization of receptors on the pharmacology are mainly unknown. Thus, subtype selectivity and favorable pharmacokinetics alone are insufficient to propose a new clinical candidate. To address these needs, the predictive value and limitations of homology modeling were analyzed in light of the X-ray structure of the A2AAR in support of structure-based drug design. At the A3AR, we designed and synthesized novel Purinergic Signalling (2010) 6:49–115 DOI 10.1007/s11302-009-9171-1