Open AccessIdentification and characterization of an atypical Gαs-biased β 2 AR agonist that fails to evoke airway smooth muscle cell tachyphylaxis
Author(s) -
Donghwa Kim,
А. Ю. Токмакова,
Lauren K. Lujan,
Hannah R. Strzelinski,
Nicholas Kim,
Maliheh Najari Beidokhti,
Marc Giulianotti,
Amirhossein Mafi,
Jung A. Woo,
Steven S. An,
William A. Goddard,
Stephen B. Liggett
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2026668118
Subject(s) - agonist , chemistry , context (archaeology) , receptor , g protein coupled receptor , arrestin , desensitization (medicine) , adenylyl cyclase , biophysics , signal transduction , tachyphylaxis , functional selectivity , cyclic adenosine monophosphate , endocrinology , medicine , microbiology and biotechnology , biology , biochemistry , paleontology
Significance We sought β2 AR agonists for treating obstructive lung diseases such as asthma, in which this receptor relaxes airway smooth muscle (ASM) cells and opens airways. Agonists favoring Gs coupling (leads to airway relaxation) compared with activating β-arrestin (limits effectiveness due to receptor desensitization) were pursued in a 40-million-compound screening library. Of several agonists identified, one was apparently biased away from β-arrestin. Agonist–receptor–G protein modeling revealed different receptor interactions compared with other agonists. The favorable effects of the apparent biasing with this agonist were demonstrated in a physiologic system (ASM relaxation). These studies point to a different structural class of β-agonists that might be used to treat obstructive lung diseases without the adverse effects associated with tachyphylaxis.