TRPM2 inhibitors(Zhejiang University)

Proper functioning of the endothelial barrier is crucial for cardiovascular system homeostasis. Oxidative stress can lead to endothelial dysfunction (ED), damaging lipids, proteins, and DNA. Reactive oxygen species also increase cytoplasmic Ca²⁺ levels, activating transient receptor potential melastatin 2 (TRPM2), a membrane non-selective calcium channel. The study aimed to assess TRPM2's significance in vascular endothelial cells' response to oxidative stress and the potential use of TRPM2 direct and indirect inhibitors in the prevention of oxidative stress-induced ED.

EA.hy926 endothelial cells were exposed to hydrogen peroxide for 24 ​h to mimic oxidative stress conditions. To assess the significance of TRPM2 in the response of EA.hy926 ​cells to hydrogen peroxide TRPM2 siRNA as well as direct (N-(p-Amylcinnamoyl)anthranilic acid, flufenamic acid) and indirect (3-aminobenzamide, 3,4-dihydro-5[4-(1-piperidinyl)butyl]-1(2H)-isoquinolinone) TRPM2 inhibitors were tested.

Results showed that hydrogen peroxide-induced ED is alleviated by TRPM2 downregulation. Moreover, preincubation of cells with both direct and indirect TRPM2 inhibitors for 30 ​min before hydrogen peroxide treatment reduces its negative effects on cell viability, cell migration, and junctional proteins.

The obtained results suggest that TRPM2 channel may be a potential target in therapy and prevention of cardiovascular diseases connected with oxidative stress-induced ED. However, further research is needed for clinical applications of direct and indirect TRPM2 inhibitors.

Studies on specific transient receptor potential melastatin 2 (TRPM2) channel inhibitors can deepen our understanding of the pathological mechanism of related diseases, and allow discovery of novel, effective targets and drugs for therapy. The development of TRPM2 channel inhibitors can be broadly classified into four categories with distinct characteristics: reutilization and structural modification of homologous ion channel modulators to produce a diverse array of TRPM2 channel inhibitors with strong inhibitory effects; TRPM2 channel inhibitors based on channel gating mechanism with high specificity; inhibitors identified through high-throughput screening with novel chemical structures; inhibitors developed from natural antioxidants with higher safety. In recent years, the application of computer-aided drug design has significantly accelerated the development of TRPM2 channel inhibitors. Several promising compounds such as ZA18, A1 and D9 have been discovered, and it is expected that more potent and selective TRPM2 channel inhibitor scaffolds will be discovered in the future. This article reviews the advances on the studies of TRPM2 channel inhibitors, aiming to provide insights for further research and clinical application of TRPM2 channel inhibitors.