RNA Therapeutics, Roche, Nutley, New Jersey 07110, USA.
Br J Pharmacol. 2010 Nov;161(6):1329-42. doi: 10.1111/j.1476-5381.2010.00975.x.
Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC(1) and VPAC(2). RO5024118 is a selective VPAC(2) receptor agonist derived via chemical modification of an earlier VPAC(2) agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118.
Stability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model.
RO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting β-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting β-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8(+) cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation.
These results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases.
This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.
血管活性肠肽在呼吸道中表达，并通过其受体 VPAC(1) 和 VPAC(2) 发挥作用。RO5024118 是一种选择性的 VPAC(2) 受体激动剂，通过对早期 VPAC(2) 激动剂 RO0251553 的化学修饰而衍生。在本研究中，我们对 RO5024118 的药理学活性进行了表征。
评估了 RO5024118 对人中性粒细胞弹性蛋白酶的稳定性。在豚鼠和人离体气道平滑肌标本以及豚鼠支气管收缩模型中研究了 RO5024118 的支气管扩张活性。在脂多糖小鼠模型和猪胰弹性蛋白酶 (PPE) 大鼠模型中研究了 RO5024118 的肺部抗炎活性。
与 RO0251553 相比，RO5024118 对中性粒细胞弹性蛋白酶的稳定性增加。在人及豚鼠离体气道标本中，RO5024118 诱导的支气管扩张作用与 RO0251553 和长效β-激动剂沙美特罗相当，且比天然血管活性肠肽和短效β-激动剂沙丁胺醇更有效。在 5-HT 诱导的豚鼠支气管收缩中，RO5024118 表现出与 RO0251553 相似的抑制活性，作用持续时间更长。在脂多糖小鼠模型中，RO5024118 抑制中性粒细胞和 CD8(+)细胞以及髓过氧化物酶水平。在大鼠中，气管内滴注 PPE 诱导气道中性粒细胞增多，对地塞米松有抗性。RO5024118 预处理可显著抑制 PPE 诱导的中性粒细胞聚集。
这些结果表明，RO5024118 诱导双重支气管扩张和肺部抗炎活性，可能有益于治疗气道阻塞性和炎症性疾病。
本文是药物发现中分析受体药理学专题的一部分。要查看本部分中的其他文章，请访问 http://dx.doi.org/10.1111/bph.2010.161.issue-6。
