期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：49
DOI：10.1073/pnas.2026668118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
We sought β
2AR 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.
G protein–coupled receptors display multifunctional signaling, offering the potential for agonist structures to promote conformational selectivity for biased outputs. For β
2-adrenergic receptors (β
2AR), unbiased agonists stabilize conformation(s) that evoke coupling to Gαs (cyclic adenosine monophosphate [cAMP
