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• W4377029246 abstract "<b>Abstract ID 14763</b> <b>Poster Board 289</b> The β2-adrenergic receptor (β2AR) is implicated in numerous physiological functions. It is activated by endogenous catecholamines and primarily signals via the canonical Gs-adenylyl cyclase-cAMP-PKA pathway. In parallel, G protein-coupled receptor kinases (GRKs) and β-arrestins regulate β2AR signaling by promoting β2AR desensitization and internalization, as well as downstream signaling often antithetical to the canonical pathway. Exogenous β-agonists, by targeting the β2AR, are the primary therapeutic medications in the treatment of asthma. This class of drugs has shown good efficiency in relieving bronchoconstriction, but patients can also experience severe side effects, ultimately worsening asthmatic attacks. Several studies have correlated the bronchodilation effects of β-agonists with activation of Gs signaling, while side effects were associated with β-arrestin functions. Recently, we reported that Gs-biased agonists for the β2AR may provide a strategy to improve the functional consequences of β2AR activation in treating airway diseases. However, since these agonists were not subtype-selective, we also focused on identifying allosteric modulators for the β2AR, since such molecules are often subtype-selective and can bias signaling. To this end, we screened small molecule libraries for allosteric modulators that selectively inhibit β-arrestin recruitment to the β2AR. This screen identified several compounds with the required profile, and of these, DFPQ was found to be a selective negative allosteric modulator of β-arrestin recruitment to the β2AR while having no effect on β2AR coupling to Gs. DFPQ effectively inhibited GRK-mediated phosphorylation as well as agonist-promoted internalization of the β2AR and protected against the functional desensitization of β-agonist-mediated regulation in cell and tissue models. The effects of DFPQ were also specific to the β2AR showing minimal effects with other GPCRs, including the structurally related β1AR. Molecular modeling, mutagenesis, and medicinal chemistry studies support DFPQ and DFPQ derivatives binding to an intracellular region of the β2AR, including residues within transmembrane domains 3 and 4 and intracellular loop 2. Thus, DFPQ represents a novel class of biased allosteric modulators that targets an intracellular allosteric site of the β2AR. The pharmacological characteristics of DFPQ can pave the way for the design of safer drugs for treating asthma and may elucidate the mechanisms behind receptor-biased signaling." @default.
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• W4377029246 date "2023-05-18" @default.
• W4377029246 modified "2023-09-29" @default.
• W4377029246 title "Identification and pharmacological characterization of a novel β-arrestin-biased negative allosteric modulator of the β" @default.
• W4377029246 doi "https://doi.org/10.1124/jpet.122.147630" @default.
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