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 G_q 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.