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β₁ adrenergic receptors (β₁ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein–coupled receptor family, β₁ARs activate cellular signaling by primarily coupling to Gs proteins to activate adenylyl cyclase, cAMP-dependent pathways, and the multifunctional adaptor-transducer protein β-arrestin. Carvedilol, a traditional β-blocker widely used in treating high blood pressure and heart failure by blocking β adrenergic receptor–mediated G protein activation, can selectively stimulate Gs-independent β-arrestin signaling of β adrenergic receptors, a process known as β-arrestin–biased agonism. Recently, a DNA-encoded small-molecule library screen against agonist-occupied β₂ adrenergic receptors (β₂ARs) identified Compound-6 (Cmpd-6) to be a positive allosteric modulator for agonists on β₂ARs. Intriguingly, it was further discovered that Cmpd-6 is …