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.

中文翻译：

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靶向激动剂来源的血管紧张素 II 受体、β-arrestin 偏倚激动剂和拮抗剂的荧光配体的合成和药理学表征


血管紧张素 II （AngII） 调节脑循环，并以与 AT₁ 和 AT₂ 受体相似的亲和力结合。偏倚的 AT₁ 激动剂，如 TRV027，能够在阻断 G_q 通路的同时选择性地激活 β-arrestin，作为新疗法似乎很有希望。需要新的药理学工具来进一步探索偏倚的 AT₁ 激动剂对细胞或组织（如脑血管）的影响。我们设计并合成了基于 AngII 、 TRV027 或 AT₁ 拮抗剂氯沙坦的新型荧光衍生物。我们进行了药理学表征，以确定它们的选择性、效力以及激活或不激活细胞和脑动脉中特异性 AT₁ 转导通路的能力。我们报道了第一个基于氯沙坦的高 AT₁ 选择性荧光配体，它以高亲和力保留其拮抗剂活性。TRV027 的荧光衍生物变为 AT₂ 选择性并失去其 AT₁ β-arrestin 偏倚。这些新配体可用于体外和体外追踪 AT₁ 或 AT₂ 受体。