ML335

ML335 is a small molecule activator of the TREK-1 (KCNK2) and TREK-2 (KCNK10) two-pore domain potassium (K2P) channels. It functions as a direct agonist by binding to the Keystone site, a pocket located behind the selectivity filter, which stabilizes the open state of the channel's C-type gate. In preclinical research, ML335 has been investigated for its protective role in respiratory conditions, specifically *Pseudomonas aeruginosa* pneumonia. By activating TREK-1 channels, ML335 induces membrane hyperpolarization in alveolar epithelial and endothelial cells, which inhibits the opening of voltage-gated calcium channels. This mechanism leads to a reduction in intracellular calcium levels, subsequently decreasing the secretion of pro-inflammatory cytokines (such as IL-6, IP-10, and MCP-1) and mitigating oxidative stress.