Allosteric modulator potentiates β2AR agonist-promoted bronchoprotection in asthma models

Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled beta 2-adrenergic receptor (beta 2AR) agonists (beta 2-agonists) promote - with limited efficacy - bronchodilation in asthma. All beta 2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a beta 2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on beta 2AR-mediated bronchoprotection. Consistent with our findings using human beta 2ARs, Cmpd-6 allosterically potentiated beta 2-agonist binding to guinea pig beta 2ARs and downstream signaling of beta 2ARs. In contrast, Cmpd-6 had no such effect on murine beta 2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced beta 2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated beta 2 agonist- mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced beta 2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of beta 2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.

Automated summary

This article investigates the potential of β2AR-selective positive allosteric modulators (PAMs) in the treatment of asthma and other obstructive respiratory diseases. The results demonstrate that these PAMs can enhance the binding and downstream signaling of β2-agonists to β2ARs in guinea pigs and humans, thereby promoting bronchodilation and protection.