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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.

The design of bifunctional compounds is a promising approach toward the development of strong analgesics with reduced side effects. We here report the optimization of the previously published lead peptide KGFF09 , which contains opioid receptor agonist and neuropeptide FF receptor antagonist pharmacophores and is shown to induce potent antinociception and reduced side effects. We evaluated the novel hybrid peptides for their in vitro activity at MOP, NPFFR1, and NPFFR2 and selected four of them ( DP08/14/32/50 ) for assessment of their acute antinociceptive activity in mice. We further selected DP32 and DP50 and observed that their antinociceptive activity is mostly peripherally mediated; they produced no respiratory depression, no hyperalgesia, significantly less tolerance, and strongly attenuated withdrawal syndrome, as compared to morphine and the recently FDA-approved TRV130. Overall, these data suggest that MOP agonist/NPFF receptor antagonist hybrids might represent an interesting strategy to develop novel analgesics with reduced side effects.