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 AT1 and AT2 receptors. Biased AT1 agonists, such as TRV027, which are able to selectively activate β-arrestin while blocking the Gq pathway, appear promising as new therapeutics. New pharmacological tools are needed to further explore the impact of biased AT1 agonists on cells or tissues, such as the cerebral vessels. We designed and synthesized new fluorescent derivatives based on AngII, TRV027, or the AT1 antagonist losartan. We conducted pharmacological characterization to determine their selectivity, potency, and ability to activate or not specific AT1 transduction pathways in cells and cerebral arteries. We report the first highly AT1-selective fluorescent ligand, based on losartan, that retains its antagonist activity with high affinity. Fluorescent derivatives of TRV027 become AT2-selective and lose their AT1 β-arrestin bias. These new ligands can be applied to trace AT1 or AT2 receptors in vitro and ex vivo.