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 1 and AT 2 receptors. Biased AT 1 agonists, such as TRV027, which are able to selectively activate β-arrestin while blocking the G q pathway, appear promising as new therapeutics. New pharmacological tools are needed to further explore the impact of biased AT 1 agonists on cells or tissues, such as the cerebral vessels. We designed and synthesized new fluorescent derivatives based on AngII, TRV027, or the AT 1 antagonist losartan. We conducted pharmacological characterization to determine their selectivity, potency, and ability to activate or not specific AT 1 transduction pathways in cells and cerebral arteries. We report the first highly AT 1 -selective fluorescent ligand, based on losartan, that retains its antagonist activity with high affinity. Fluorescent derivatives of TRV027 become AT 2 -selective and lose their AT 1 β-arrestin bias. These new ligands can be applied to trace AT 1 or AT 2 receptors in vitro and ex vivo.