Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M_3 Receptor Antagonist/β_2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile

摘要

AZD8871 is a novel muscarinic antagonist and β2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M_3 receptor (pIC_(50) in binding assays: 9.5) and shows kinetic selectivity for the M_3 (half-life: 4.97 hours) over the M_2 receptor (half-life: 0.46 hour). It is selective for the β2-adrenoceptor over the b1 and b3 subtypes β- and 6-fold, respectively) and shows dual anti-muscarinic and β2-adrenoceptor functional activity in isolated guinea pig tissue (pIC_(50) in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchocon-striction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M_3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.