Identification and characterization of an atypical Gαs-biased β₂AR agonist that fails to evoke airway smooth muscle cell tachyphylaxis.

ABSTRACT: G protein-coupled receptors display multifunctional signaling, offering the potential for agonist structures to promote conformational selectivity for biased outputs. For β₂-adrenergic receptors (β₂AR), unbiased agonists stabilize conformation(s) that evoke coupling to Gαs (cyclic adenosine monophosphate [cAMP] production/human airway smooth muscle [HASM] cell relaxation) and β-arrestin engagement, the latter acting to quench Gαs signaling, contributing to receptor desensitization/tachyphylaxis. We screened a 40-million-compound scaffold ranking library, revealing unanticipated agonists with dihydroimidazolyl-butyl-cyclic urea scaffolds. The S-stereoisomer of compound C1 shows no detectable β-arrestin engagement/signaling by four methods. However, C1-S r

SUBMITTER: Kim D 

PROVIDER: S-EPMC8670521 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature