Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABA(A) Receptor Modulators.
Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABA(A) Receptor Modulators.
复制标题
DOI：
10.1021/acs.molpharmaceut.7b00183
复制
发表时间：
2017-06-05
影响因子：
4.9
通讯作者：
Arnold LA
中科院分区：
文献类型：
--
作者：
Forkuo GS;Nieman AN;Yuan NY;Kodali R;Yu OB;Zahn NM;Jahan R;Li G;Stephen MR;Guthrie ML;Poe MM;Hartzler BD;Harris TW;Yocum GT;Emala CW;Steeber DA;Stafford DC;Cook JM;Arnold LA
我们描述了两种新型口服哮喘候选药物的药代动力学和药效学特性。酚类 α4β3γ2 GABAAR 选择性化合物 1 和酸性 α5β3γ2 选择性 GABAAR 正变构调节剂化合物 2 可在小鼠哮喘模型中离体放松气道平滑肌并减弱气道高反应性 (AHR)。重要的是，化合物2松弛乙酰胆碱收缩人气管气道平滑肌条。口服化合物1和2可减少卵清蛋白致敏和攻击小鼠支气管肺泡灌洗液中的嗜酸性粒细胞，从而表现出抗炎特性。此外，化合物 1 减少了肺 CD4+ T 淋巴细胞的数量，并通过作用于 GABAAR 直接调节其跨膜电流。观察到优异的药代动力学特性，包括长血浆半衰期（长达 15 小时）、口服利用度和极低的脑分布。总之，我们报告了脑外表达的 GABAAR 的选择性靶向，并证明两种新型口服 GABAAR 配体可减少 AHR 和气道炎症。
We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic α4β3γ2 GABAAR selective compound 1 and acidic α5β3γ2 selective GABAAR positive allosteric modulator compound 2 relaxed airway smooth muscle ex vivo and attenuated airway hyperresponsiveness (AHR) in a murine model of asthma. Importantly, compound 2 relaxed acetylcholine contracted human tracheal airway smooth muscle strips. Oral treatment of compound 1 and 2 decreased eosinophils in bronchoalveolar lavage fluid in ovalbumin sensitized and challenged mice, thus exhibiting anti-inflammatory properties. Additionally, compound 1 reduced the number of lung CD4+ T lymphocytes and directly modulated their transmembrane currents by acting on GABAARs. Excellent pharmacokinetic properties were observed, including long plasma half-life (up to 15 hours), oral availability, and extremely low brain distribution. In conclusion, we report the selective targeting of GABAARs expressed outside the brain and demonstrate reduction of AHR and airway inflammation with two novel orally available GABAAR ligands.