Pharmacology of a novel TRPM2 antagonist, JNJ-28583113

TRPM2 is a calcium-permeable non-selective cation channel that is activated, in a synergistic manner, by both intracellular adenosine diphosphate ribose (ADPR) and calcium. It is also activated indirectly by reactive oxygen nitrogen species (ROS/NOS) due to increased ADPR production during oxidative/nitrosative stress. TRPM2 is primarily expressed in the immune cells and central nervous system (CNS) where it plays important roles in pathologies involving neuroimmune interactions, particularly in the context of oxidative stress. Within the CNS, TRPM2 is expressed mainly in neurons and microglia. Here, we present the pharmacological properties of JNJ-28583113, a newly discovered compound representing the most potent TRPM2 antagonist described to date. Our data show that this compound has a potency range of 100–200 nM in blocking H2O2-induced calcium flux in several recombinant systems over-expressing human, chimpanzee and rat TRPM2. In whole-cell patch clamp recordings, JNJ-285831113 blocked intracellular A...