Novel 2-Aminobenzimidazole Derivatives: Inhibitors of TRPC4 and TRPC5 Channels

The study focuses on the role of Transient receptor potential canonical (TRPC) channels in physiological processes and diseases, which has been difficult to define due to the absence of potent and specific inhibitors. Researchers have utilized fluorescence assays and electrophysiological techniques to characterize new small molecule inhibitors, derived from 2-aminobenzimidazole, targeting TRPC4 and TRPC5 channels discovered through high-throughput screening.

The initial compound, M084, showed strong inhibitory effects on TRPC4 and TRPC5, while having a weaker impact on TRPC3. Further structural modifications led to the development of more potent and selective analogues for the TRPC4 and TRPC5 channels. These derivatives were found to rapidly suppress TRPC4 and TRPC5-mediated currents when applied extracellularly, regardless of the channels' activation mode. They were also effective in blocking the plateau potential in mouse neurons caused by TRPC4 channels, without affecting other related TRP channels or native voltage-gated sodium, potassium, and calcium channels.

The development of these TRPC4/C5-selective inhibitors offers new and valuable tools for the study of the physiological and pathophysiological roles of TRPC4 and TRPC5 channels.