Key result
Novel AT1 receptor ligand R781253 acts as a biased agonist, stimulating ERK1/2 while inhibiting inositol phosphate.
Why the study?
Peptide AT1 receptor ligands act as biased agonists by antagonizing Ang II-stimulated G protein signaling while stimulating kinase pathways, prompting the development of non-peptide AT1 receptor biased ligands.
Structural modification of existing AT1 receptor blockers can yield non-peptide biased ligands that selectively modulate intracellular signaling pathways, representing a potential novel approach for targeted cardiovascular therapeutics.
Hypothesis-generating for biased non-peptide AT1 ligands; leaves open translation to cardiovascular therapeutics.
As a biased agonist, peptide angiotensin II (Ang II) type 1 (AT1) receptor ligand antagonizes Ang II-stimulated G protein signaling but stimulates several kinase pathways. Here, we developed a non-peptide AT1 receptor compound as a biased ligand. We synthesized three non-peptide AT1 receptor ligands (R239470, R781253, and R794847) as candidates of biased ligands. Extracellular signal-regulated kinase (ERK) 1/2 activation and inositol phosphate (IP) production were measured using a cell system that overexpressed AT1 receptors (wild-type, L112A, Q257A, Y292A, and N295A receptors). We also examined the modes of receptor–ligand binding using a competition binding study. The Kd values of R239470, R781253, and R794847 for the AT1 wild-type receptor were 0.8, 21, and 48 nM, respectively, as assessed in a competition binding study. Those of R239470, R781253, and R794847 for the L112A receptor were 37, 23, and 31 nM, respectively. R781253 and R794847 decreased and increased IP production, respectively, whereas R239470 did not change IP production. R781253 and R794847, but not R239470, activated ERK1/2. In conclusion, R239470, R781253, and R794847 act as a neutral antagonist, an inverse agonist, and an agonist with regard to IP production, respectively. On the other hand, R781253 and R794847, but not R239470, are agonists toward ERK1/2 activation. Thus, we developed a non-peptide AT1 receptor compound as a biased ligand.
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Matsuo et al. (2023) studied In vitro (Basic Science). Non-peptide AT1 receptor ligands (R239470, R781253, and R794847) vs. Olmesartan, Angiotensin II, or basal conditions was evaluated on Binding affinity (Kd), inositol phosphate (IP) production, and ERK1/2 activation. The structurally modified compound R781253 acted as a biased ligand, demonstrating inverse agonism for inositol phosphate production while acting as an agonist for ERK1/2 activation.
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