Discovery of novel TRPC5 inhibitors by systematic structural modulation and activity validation

Transient Receptor Potential Canonical 5 (TRPC5) ion channels are promising therapeutic targets for anxiety, kidney disease, and seizures. Starting from the hit compound BY-2 (IC₅₀ = 1.78 μM), we performed targeted structural modifications on its three key regions (A, B, C) to develop more potent TRPC5 inhibitors. In vitro assays identified two derivatives, 9A1 (IC₅₀ = 0.77 μM) and 11B1 (IC₅₀ = 1.73 μM), with superior potency to BY-2 and the positive control Clemizole (CMZ, IC₅₀ = 1.27 μM). Structure-activity relationship (SAR) analysis indicated that bulky hydrophobic and polar substituents in region B enhanced activity, while excessive modifications in A/C reduced activity. Molecular docking (PDB ID: 7D4P) showed 9A1/11B1 formed stable interactions with TRPC5's VSLD allosteric pocket. Animal tests confirmed 9A1 exerted significant anxiolytic effects in C57BL/6 mice. Thus, 9A1 is a promising lead compound for TRPC5-related disease therapeutics.