Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists.

Angiotensin II (AngII) regulates cerebral circulation and binds with a similar affinity to AT and AT receptors. Biased AT agonists, such as TRV027, which are able to selectively activate β-arrestin while blocking the G pathway, appear promising as new therapeutics. New pharmacological tools are needed to further explore the impact of biased AT agonists on cells or tissues, such as the cerebral vessels. We designed and synthesized new fluorescent derivatives based on AngII, TRV027, or the AT antagonist losartan. We conducted pharmacological characterization to determine their selectivity, potency, and ability to activate or not specific AT transduction pathways in cells and cerebral arteries. We report the first highly AT-selective fluorescent ligand, based on losartan, that retains its antagonist activity with high affinity. Fluorescent derivatives of TRV027 become AT-selective and lose their AT β-arrestin bias. These new ligands can be applied to trace AT or AT receptors in vitro and ex vivo.