Safety issues of compounds acting on adenosinergic signalling

OBJECTIVES: Much research has been performed on the field of identifying the roles of adenosine and adenosinergic signalling, but a relatively low number of marketing authorizations have been granted for adenosine receptor (AdR) ligands. In part, this could be related to their safety issues; therefore, our aim was to examine the toxicological and adverse effects data of different compounds acting on adenosinergic signalling, including different AdR ligands and compounds resembling the structure of adenosine. We also wanted to present recent pharmaceutical developments of experimental compounds that showed promising results in clinical trial setting. KEY FINDINGS: Safety issues of compounds modulating adenosinergic signalling were investigated, and different mechanisms were presented. Structurally different classes of compounds act on AdRs, the most important being adenosine, adenosine derivatives and other non-nucleoside compounds. Many of them are either not selective enough or are targeting other targets of adenosinergic signalling such as metabolizing enzymes that regulate adenosine levels. Many other targets are also involved that are not part of adenosinergic signalling system such as GABA receptors, different channels, enzymes and others. Some synthetic AdR ligands even showed to be genotoxic. SUMMARY: Current review presents safety data of adenosine, adenosine derivatives and other non-nucleoside compounds that modulate adenosinergic signalling. We have presented different mechanisms that participate to an adverse effect or toxic outcome. A separate section also deals with possible organ-specific toxic effects on different in-vitro and in-vivo models.