Selective Activation of a TRPC6 Ion Channel Over TRPC3 by Metalated Type-B Polycyclic Polyprenylated Acylphloroglucinols

• Published in: Journal of medicinal chemistry 2023-11, Vol.66 (22), p.15061-15072
• Main Authors: Peslalz, Philipp, Kraus, Frank, Izzo, Flavia, Bleisch, Anton, El Hamdaoui, Yamina, Schulz, Ina, Kany, Andreas M, Hirsch, Anna K H, Friedland, Kristina, Plietker, Bernd
• Format: Article
• Language: English
• Subjects: Binding Sites; Cryoelectron Microscopy; Ketones - chemistry; Ketones - pharmacology; Phloroglucinol - pharmacology; Polycyclic Compounds - pharmacology; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; TRPC Cation Channels - drug effects; TRPC Cation Channels - metabolism; TRPC6 Cation Channel - drug effects
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01170

Selective modulation of TRPC6 ion channels is a promising therapeutic approach for neurodegenerative diseases and depression. A significant advancement showcases the selective activation of TRPC6 through metalated type-B PPAP, termed . This success stems from 's 1,3-diketone motif facilitating metal coordination. is water-soluble and as potent as hyperforin, the gold standard in this field. In contrast to type-A, type-B PPAPs offer advantages such as gram-scale synthesis, easy derivatization, and long-term stability. Our investigations reveal selectively binding to the C-terminus of TRPC6. Although cryoelectron microscopy has resolved the majority of the TRPC6 structure, the binding site in the C-terminus remained unresolved. To address this issue, we employed state-of-the-art artificial-intelligence-based protein structure prediction algorithms to predict the missing region. Our computational results, validated against experimental data, indicate that binds to the LLKL -region of the C-terminus, thus providing critical insights into the binding mechanism of .