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The β₁ adrenergic receptor (β₁AR) 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 β₂AR. 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 β₂AR and the β₁AR, while having minimal effect on the affinity of a panel of agonists and antagonists of the β₁AR …