New paradigms in purinergic receptor ligand discovery

Neuropharmacology. 2023 Mar 13:109503. doi: 10.1016/j.neuropharm.2023.109503. Online ahead of print.ABSTRACTThe discovery and clinical implementation of modulators of adenosine, P2Y and P2X receptors have progressed dramatically in ∼50 years since Burnstock's definition of purinergic signaling. Although most clinical trials of selective ligands (agonists and antagonists) of these nineteen receptors failed, there is a renewed impetus to redirect efforts to new disease conditions and the discovery of more selective or targeted compounds with potentially reduced side effects, such as biased GPCR agonists. The elucidation of new receptor and enzyme structures is steering rational design of potent and selective agonists, antagonists, allosteric modulators and inhibitors. A2A adenosine receptor (AR) antagonists are being applied to neurodegenerative conditions and cancer immunotherapy. A3AR agonists have potential for treating chronic inflammation (e.g. psoriasis), stroke and pain, as well as cancer. P2YR modulators are being considered for treating inflammation, metabolic disorders, acute kidney injury, cancer, pain and other conditions, often with an immune mechanism. ADP-activated P2Y12R antagonists are widely used as antithrombotic drugs, while their repurposing toward neuroinflammation is considered. P2X3 antagonists have been in clinical trials for chronic cough. P2X7 antagonists have been in clinical trials for inflammatory diseases and depression (compounds that penetrate...
Source: Neuropharmacology - Category: Drugs & Pharmacology Authors: Source Type: research