Almirall, Research & Development Center, Sant Feliu de Llobregat, Barcelona, Spain (M.A., C.C., I.R., J.L.M., R.O., C.P., D.V., J.D.A., C.D., A.G., M.M.); and Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain (J.L.O., J.C.)
Almirall, Research & Development Center, Sant Feliu de Llobregat, Barcelona, Spain (M.A., C.C., I.R., J.L.M., R.O., C.P., D.V., J.D.A., C.D., A.G., M.M.); and Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain (J.L.O., J.C.).
J Pharmacol Exp Ther. 2019 Jul;370(1):127-136. doi: 10.1124/jpet.118.255620. Epub 2019 May 13.
AZD8871 is a novel muscarinic antagonist and -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 receptor (pIC in binding assays: 9.5) and shows kinetic selectivity for the M (half-life: 4.97 hours) over the M receptor (half-life: 0.46 hour). It is selective for the -adrenoceptor over the and subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and -adrenoceptor functional activity in isolated guinea pig tissue (pIC in electrically stimulated trachea: 8.6; pEC 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 bronchoconstriction 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 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.
AZD8871 是一种新型的毒蕈碱拮抗剂和β-肾上腺素受体激动剂，用于治疗慢性阻塞性肺疾病。本研究描述了 AZD8871 在体外和体内测定中的药理学特征。AZD8871 对人 M 受体具有强大的亲和力（在结合测定中的 pIC：9.5），并且对 M 受体（半衰期：4.97 小时）具有动力学选择性，而对 M 受体（半衰期：0.46 小时）则没有选择性。它对β-肾上腺素受体具有选择性，对β1 和β3 亚型的选择性分别为 3 倍和 6 倍，并且在分离的豚鼠组织中具有双重抗毒蕈碱和β-肾上腺素能受体功能活性（在电刺激气管中的 pIC：8.6；在自发张力分离气管中的 pEC：8.8），随着时间的推移持续存在。AZD8871 在人支气管中显示出比巴替非特更强的毒蕈碱成分，在普萘洛尔阻断下效力分别增加了 2 倍和 6 倍，同时保持松弛（8 小时时恢复 5.3%）。雾化 AZD8871 可预防乙酰胆碱诱导的豚鼠和犬支气管收缩，在具有支气管保护活性的剂量下对唾液分泌和心率的影响最小。此外，AZD8871 在犬中显示出持久的作用，其支气管保护半衰期长于 24 小时。总之，这些研究表明，AZD8871 是一种具有高毒蕈碱成分和 M 受体长停留时间的双重作用分子；此外，其在动物模型中的临床前特征表明，在人类中每天一次给药和良好的安全性特征。因此，AZD8871 有可能成为治疗呼吸道疾病的新一代吸入性支气管扩张剂。
