Abstract
The obstructive lung diseases (OLDs), such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by bronchoconstriction and difficulty in breathing. β(2)-adrenergic receptor (β(2)AR) agonists (β-agonists) represent the most commonly used class of bronchodilators. To enhance their clinical effectiveness, extensive attempts have been made to improve their receptor subtype selectivity and duration of action, resulting in the development of long-acting β-agonists (LABAs) and ultralong-acting β-agonists. Although these drugs effectively alleviate OLD symptoms, concerns have arisen regarding their safety, their reduced therapeutic benefits, and the potential for worsening asthma symptoms. These concerns have led to restrictions on β-agonist use. Recent advances in G protein-coupled receptor (GPCR) pharmacology and biochemistry have introduced new concepts in drug development, such as "biased agonism" and "allosteric modulation." These advancements stem from a deeper understanding of the molecular interactions between β(2)ARs and various intracellular proteins (e.g., heterotrimeric G proteins and β-arrestins), which induce a diverse array of functional changes in airway cells. Biased agonism and allosteric modulation offer new avenues for developing the next generation of β-agonists with improved pharmacological properties. This review explores the application of these concepts in developing new β(2)AR ligands, including orthosteric and allosteric ligands, that selectively enhance therapeutically beneficial Gs signaling while minimizing harmful β-arrestin-mediated effects in airway cells.