Modulators of Piezo1

Piezo1 is a mechanosensitive ion channel involved in vascular development, stem cell lineation and endothelial cell homeostasis. It allows movement of cations into the cell in response to mechanical forces, such as membrane stretching. Piezo1 is non-selective between sodium, lithium and calcium, but calcium has a much larger extracellular gradient compared to the others. Because of the high concentration gradient, calcium is a key signalling molecule in biology. Mechanical activation of Piezo1 causes calcium entry into the cell, which can then lead to various cellular responses to mechanical stress.
The first chemical agonist of Piezo1 was discovered in 2015, termed Yoda1. Until then Piezo1 had to be studied using mechanical forces such as shear flow, membrane stretching and mechanical indentation. This makes Yoda1 a key tool molecule for studying Piezo1, as experiments can be run without mechanical forces. Yoda1 has played a significant role in studying Piezo1, but it has a rather poor potency of EC50 of 17-27 μM and has poor physicochemical and ADME properties, limiting its usefulness particularly in an in vivo setting.
The aim of this work was to develop tool compounds for studying Piezo1. Yoda1 was the inspiration for developing compounds with improved potency and drug-like properties as well as compounds with novel pharmacology. During the course of this work I elucidated a good understanding of the structure activity relationships of Yoda1 and its analogues. Compounds have also shown novel pharmacology by inhibiting or increasing Yoda1 activation and by increasing the Piezo1 response to mechanical forces. A compound has also been identified with improved potency and drug-like properties compared to Yoda1. This compound was then used in the first in vivo studies of Piezo1 using a chemical activator.