Improved PIEZO1 agonism through 4-benzoic acid modification of Yoda1.

ABSTRACT:

Background and purpose

The protein PIEZO1 forms mechanically activated, calcium-permeable, non-selective cation channels in numerous cell types from several species. Options for pharmacological modulation are limited and so we modified a small-molecule agonist at PIEZO1 channels (Yoda1) to increase the ability to modulate these channels.

Experimental approach

Medicinal chemistry generated Yoda1 analogues that were tested in intracellular calcium and patch-clamp assays on cultured cells exogenously expressing human or mouse PIEZO1 or mouse PIEZO2. Physicochemical assays and wire myography assays on veins from mice with genetic disruption of PIEZO1.

Key results

A Yoda1 analogue (KC159) containing 4-benzoic acid instead of the pyrazine of Yoda1 and its potassium salt (KC

SUBMITTER: Parsonage G 

PROVIDER: S-EPMC10952572 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature