Development of Inhaled GABAA Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders.
Development of Inhaled GABAA Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders.
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开发吸入 GABAA 受体调节剂以改善支气管收缩性疾病的气道功能。
DOI：
10.1021/acsptsci.1c00238
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发表时间：
2022
影响因子：
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通讯作者：
Arnold,LeggyA
中科院分区：
文献类型：
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作者：
Zahn,NicolasM;Roni,MSRashid;Yocum,GeneT;Meyer,MichelleJ;Webb,DanielA;Mian,MdYeunus;Cook,JamesM;Stafford,DouglasC;Emala,CharlesW;Arnold,LeggyA
我们报告了使用两个烷基取代基对 MIDD0301（一种咪唑并二氮杂 GABAA 受体（GABAAR）配体）进行的修饰。我们开发了具有 6-(4-苯基丁氧基)己基链的 PI310，用于长效 β2 激动剂沙美特罗，以及具有聚乙二醇链的 PI320，用于改善纳洛酮类似物纳洛酮的脑与血浆比例。两种咪唑并二氮卓类药物都对氯硝西泮的 GABAAR 结合位点表现出亲和力，IC50 值分别为 576 和 242 nM。使用可用的 α1β3γ2GABAAR 结构数据进行的分子对接分析表明，二氮杂卓核心在 α1+/γ2- 界面之间结合，而烷基取代基位于结合位点之外，从而与蛋白质表面和溶剂分子相互作用。这些化合物的物理化学性质非常不同。 PI310在水中的溶解度较低。 PI320 的聚乙二醇化显着提高了水溶性和细胞通透性。在 >300 μM 浓度下暴露 18 小时后，这两种化合物对 HEK293 细胞均无毒性。使用豚鼠气管环的离体研究表明，PI310 无法放松收缩的气道平滑肌。相比之下，PI320 在器官浴浓度低至 5 μM 时诱导肌肉松弛，在 25 μM 时起效迅速（15 分钟）。在由 INFγ 和脂多糖 (LPS) 气管内激发诱导的类固醇抗性肺部炎症小鼠模型中，PI320 还可降低体内气道高反应性。在 7.2 mg/kg 的雾化剂量下，PI320 和沙丁胺醇在降低气道高反应性方面同样有效。雾化后 10 分钟，PI320 的肺浓度是 PI310 的 50 倍，表明以水溶液形式雾化时 PI320 的利用率更高。总体而言，PI320 是一种有前途的吸入候选药物，可快速放松支气管收缩性疾病（例如哮喘）中的气道平滑肌。未来的研究将评估口服 PI320 的药代动力学/药效学特性。
We report the modification of MIDD0301, an imidazodiazepine GABAAreceptor (GABAAR) ligand, using two alkyl substituents. We developed PI310 with a 6-(4-phenylbutoxy)hexyl chain as used in the long-acting β2-agonist salmeterol and PI320 with a poly(ethylene glycol) chain as used to improve the brain:plasma ratio of naloxegol, a naloxone analogue. Both imidazodiazepines showed affinity toward the GABAAR binding site of clonazepam, with IC50values of 576 and 242 nM, respectively. Molecular docking analysis, using the available α1β3γ2GABAAR structural data, suggests binding of the diazepine core between the α1+/γ2– interface, whereas alkyl substituents are located outside the binding site and thus interact with the protein surface and solvent molecules. The physicochemical properties of these compounds are very different. The solubility of PI310 is low in water. PEGylation of PI320 significantly improves aqueous solubility and cell permeability. Neither compound is toxic in HEK293 cells following exposure at >300 μM for 18 h.Ex vivostudies using guinea pig tracheal rings showed that PI310 was unable to relax the constricted airway smooth muscle. In contrast, PI320 induced muscle relaxation at organ bath concentrations as low as 5 μM, with rapid onset (15 min) at 25 μM. PI320 also reduced airway hyper-responsivenessin vivoin a mouse model of steroid-resistant lung inflammation induced by intratracheal challenge with INFγ and lipopolysaccharide (LPS). At nebulized doses of 7.2 mg/kg, PI320 and albuterol were equally effective in reducing airway hyper-responsiveness. Ten minutes after nebulization, the lung concentration of PI320 was 50-fold that of PI310, indicating superior availability of PI320 when nebulized as an aqueous solution. Overall, PI320 is a promising inhaled drug candidate to quickly relax airway smooth muscle in bronchoconstrictive disorders, such as asthma. Future studies will evaluate the pharmacokinetic/pharmacodynamic properties of PI320 when administered orally.