Editorial: Purinergic pharmacology, Volume II

Abstract

Extracellular purine nucleotides and nucleosides serve as crucial signalling molecules, acting as neurotransmitters and neuromodulators. Tightly regulated extracellular levels of adenosine 5′-triphosphate (ATP) and adenosine, which are controlled by various enzymes and transporters, activate a variety of purinergic receptors. These receptors, which appear early in evolution, are among the most abundant receptors in living organisms and regulate numerous physiological processes, making them attractive therapeutic targets for a wide range of diseases. While P1 (adenosine) receptors are selective for adenosine, the breakdown product of ATP, P2 receptors respond to purine and pyrimidine nucleotides. Importantly, purinergic receptors, including both G protein-coupled receptors (ARs and P2YRs) and ligand-gated ion channel receptors (P2XRs), are involved in a multitude of neuronal and non-neuronal mechanisms, such as pain, immune responses, exocrine and endocrine secretion, platelet aggregation, endothelium-mediated vasodilatation, and inflammation. However, since purinergic receptors are widely distributed throughout the body, it is challenging to develop drugs that selectively target specific receptor subtypes without causing unwanted side effects. Additionally, extracellular levels of purines and pyrimidines can also vary greatly, leading to the simultaneous activation of different purinergic receptors in response to oscillating concentrations of endogenous purines. Consequently, through these different subtypes of P1 and P2 receptors, cells integrate extracellular purine responses, harmonising short- and long-term purinergic signalling. Therefore, the selectivity of drugs is a crucial goal in the field of purinergic pharmacology. For decades, medicinal chemists have been developing potent and selective synthetic agonists and antagonists for purinergic receptors, as well as allosteric modulators that allow for event-responsive and temporally specific manipulation of the endogenous purinergic system. Additionally, modulation of the metabolism and uptake of extracellular purine nucleotides and nucleosides can also regulate purinergic processes. Overall, the field of purinergic pharmacology is rapidly expanding and presents exciting opportunities for pharmacotherapeutic development.