Unraveling the binding site of AMG-9090 on the pain receptor TRPA1

The transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel that plays a vital role as a key receptor in the pain pathway, contributing to multiple painful conditions. Due to its significance in pain signaling, TRPA1 has emerged as a major target in the ongoing development of new and innovative analgesics. Over the past decade, multiple antagonist classes have been reported with a wide range of structural diversity. Our work has focused on a group known as trichloro(sulfanyl)ethyl benzamides, with a specific emphasis on one particular member known as AMG-9090, which acts as a potent antagonist of human TRPA1. However, AMG-9090 acts as a partial agonist on rat TRPA1. Until now, the binding site of AMG-9090 on human TRPA1 remains unknown. Therefore, we aimed to find the precise binding site of AMG-9090 on human TRPA1. Based on the species-specific effects on human and rat channels, we identified residues critical for channel modulation. Identifying the binding site of AMG-9090 and its interactions with TRPA1 may help in the development of more effective pharmaceuticals for pain management.