Abstract MP133: Development of β-arrestin-biased Positive Allosteric Modulators for the β
1
Adrenergic Receptor
Wang, J; Gokhan, I; Xiong, X; Kahsai, AW; Jiang, H; Pfeiffer, CT; Tian, W; Pani, B; Ahn, S; Lefkowitz, RJ; Rockman, HA
Published in: Circulation Research
The β
adrenergic receptor (β
AR) is a central regulator of cardiac function and an important therapeutic target for cardiac diseases. Two emerging areas of receptor biology are biased agonism: ligand directed selective engagement of a receptor toward either a G protein or β-arrestin transducer; and allosteric modulation: ligands that bind to topographically distinct sites on the receptor to modulate its activity. Advances in these areas have the potential to yield new drugs that precisely enhance cardioprotective effects while limiting untoward detrimental actions.
Compound 6 (Cmpd6) is a newly discovered positive allosteric modulator (PAM) for the β
AR. Interestingly, we now show that Cmpd6 has the unique property to enhance the binding affinity of the β-arrestin-biased agonist carvedilol to both the β
AR and the β
AR, while having minimal effect on the affinity of a panel of agonists and antagonists of the β
AR. We further tested the effect of Cmpd6 on β
AR signaling induced by a broad range of ligands. Cmpd6 selectively enhanced carvedilol-stimulated ERK activation in a β-arrestin-dependent signaling fashion, while having no effect on carvedilol-induced G protein-dependent cAMP production.
To test the
effect of Cmpd6 on cardiac injury, mice were pretreated with carvedilol with or without Cmpd6, then underwent ischemia/reperfusion through the left anterior descending artery ligation. Cell apoptosis was assessed by TUNEL. Carvedilol decreased the level of I/R-induced apoptosis compared to the vehicle-treated animals, and Cmpd6 significantly positively enhanced the anti-apoptotic effects of carvedilol.
In conclusion, we identified Cmpd6 as a potential β-arrestin-biased PAM for the β
AR that enhances the cardioprotective effect of carvedilol. Ongoing studies will test Cmpd6 on heart failure post myocardial infarction.
