Yoda1 analogue (Dooku1) which antagonizes Yoda1-evoked activation of Piezo1 and aortic relaxation.

ABSTRACT:

Background and purpose

The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist, but the pharmacology of these channels is otherwise limited.

Experimental approach

Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca²⁺ and Tl⁺ measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in HUVECs, which natively express Piezo1. Isometric tension recordings were made from rings of mouse thoracic aorta.

Key results

Modification of the pyrazine ring of Yoda1 yielded an analogue, which lacked agonist activity but reversibly antagonized Yoda1. The analogue is referred to as Dooku1. Dooku1 inhibited 2 μM Yoda1-induced Ca²⁺ -entr

SUBMITTER: Evans EL 

PROVIDER: S-EPMC5913400 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature