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<sub>1</sub> and AT<sub>2</sub> receptors. Biased AT<sub>1</sub> agonists, such as TRV027, which are able to selectively activate β-arrestin while blocking the G<sub>q</sub> pathway, appear promising as new therapeutics. New pharmacological tools are needed to further explore the impact of biased AT<sub>1</sub> agonists on cells or tissues, such as the cerebral vessels. We designed and synthesized new fluorescent derivatives based on AngII, TRV027, or the AT<sub>1</sub> antagonist losartan. We conducted pharmacological characterization to determine their selectivity, potency, and ability to activate or not specific AT<sub>1</sub> transduction pathways in cells and cerebral arteries. We report the first highly AT<sub>1</sub>-selective fluorescent ligand, based on losartan, that retains its antagonist activity with high affinity. Fluorescent derivatives of TRV027 become AT<sub>2</sub>-selective and lose their AT<sub>1</sub> β-arrestin bias. These new ligands can be applied to trace AT<sub>1</sub> or AT<sub>2</sub> receptors in vitro and ex vivo.
Authors
- Alexandra Kleinclauss (ORCID: https://orcid.org/0000-0002-9162-1288)
- Michel Boisbrun (ORCID: https://orcid.org/0000-0001-6588-0027)
- Philippe Robin (ORCID: https://orcid.org/0000-0001-5521-9454)
- Thủy Nguyễn
- Céline Delaitre
- André Dias (ORCID: https://orcid.org/0000-0002-1498-2725)
- François Dupuis (ORCID: https://orcid.org/0000-0003-1947-3839)
- Nicolas Gilles (ORCID: https://orcid.org/0000-0001-6853-9764)
- Mélissa Colin (ORCID: https://orcid.org/0000-0002-6002-1423)
- Sandra Lecat
- Mathilde Achard
- Samir Acherar (ORCID: https://orcid.org/0000-0002-8776-1632)
- Karen L. Martinez (ORCID: https://orcid.org/0000-0003-0932-8080)
- Nicolas Humbert (ORCID: https://orcid.org/0000-0002-0166-5608)
- Khawla Chmeis
Institutions
- University of Copenhagen (DK)
- Centre National de la Recherche Scientifique (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- CEA Paris-Saclay (FR)
- Laboratoire de Chimie-Physique Macromoléculaire (FR)
- Laboratoire Lorrain de Chimie Moléculaire (FR)
- Cibles thérapeutiques, formulation et expertise préclinique du médicament
- Université de Strasbourg (FR)
- Université de Lorraine (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01693
- Citations
- 1
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- Université de Lorraine
- European Cooperation in Science and Technology
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Université de Strasbourg
- Centre National de la Recherche Scientifique
- Novo Nordisk Fonden
- Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation