Identification and characterization of an atypical Gαs-biased β <sub>2</sub> AR agonist that fails to evoke airway smooth muscle cell tachyphylaxis
Donghwa Kim, А. Ю. Токмакова, Lauren K. Lujan, Hannah R. Strzelinski, Nicholas Kim, Maliheh Najari Beidokhti, Marc A. Giulianotti, Amirhossein Mafi, Jung A. Woo, Steven S. An, William A. Goddard, Stephen B. Liggett
Abstract
Significance We sought β 2 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.