Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments.
Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments.
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DOI：
10.1021/acs.molpharmaceut.6b00159
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发表时间：
2016-06-06
影响因子：
4.9
通讯作者：
Arnold LA
中科院分区：
文献类型：
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作者：
Forkuo GS;Guthrie ML;Yuan NY;Nieman AN;Kodali R;Jahan R;Stephen MR;Yocum GT;Treven M;Poe MM;Li G;Yu OB;Hartzler BD;Zahn NM;Ernst M;Emala CW;Stafford DC;Cook JM;Arnold LA
最近的研究表明，亚型选择性 GABAA 受体调节剂能够在体外放松预先收缩的人气道平滑肌，并减少气雾给药后小鼠气道高反应性。我们在这项研究中的目标是研究亚型选择性 GABAA 受体调节剂的全身给药以减轻哮喘小鼠模型中的支气管收缩。在小鼠肺部中鉴定了 GABAA 受体亚基的表达，并在小鼠哮喘模型（卵清蛋白致敏和攻击 BALB/c 小鼠）中研究了 α4 亚基选择性 GABAAR 调节剂 XHE-III-74EE 及其代谢物 XHE-III-74A 的作用。我们观察到，XHE-III-74EE 的长期治疗显着降低了气道高反应性。此外，XHE-III-74A（而非 XHE-III-74EE）急性治疗可减少气道嗜酸性粒细胞增多。在 GABA 或 XHE-III-74A 存在下，活化的人 T 细胞也显示出免疫抑制活性，IL-2 表达和细胞内钙浓度 [Ca2+]i 降低，而 XHE-III-74EE 仅显示 [Ca2+]i 部分降低，且不抑制 IL-2 分泌。然而，这两种化合物均在体外显着松弛预收缩的气管环。总体而言，我们得出的结论是，α4-亚基选择性 GABAAR 调节剂的全身递送显示出新型哮喘治疗的良好潜力，然而，必须改进此类候选药物的药代动力学特性，以实现更好的有益的全身药效学效果。
Recent studies have demonstrated that subtype-selective GABAA receptor modulators are able to relax pre-contracted human airway smooth muscle ex vivo and reduce airway hyper-responsiveness in mice upon aerosol administration. Our goal in this study was to investigate systemic administration of subtype-selective GABAA receptor modulators to alleviate bronchoconstriction in a mouse model of asthma. Expression of GABAA receptor subunits was identified in mouse lungs and the effects of α4-subunit-selective GABAAR modulators, XHE-III-74EE and its metabolite XHE-III-74A, were investigated in a murine model of asthma (ovalbumin sensitized and challenged BALB/c mice). We observed that chronic treatment with XHE-III-74EE significantly reduced airway hyper-responsiveness. In addition, acute treatment with XHE-III-74A but not XHE-III-74EE decreased airway eosinophilia. Immune suppressive activity was also shown in activated human T-cells with a reduction in IL-2 expression and intracellular calcium concentrations [Ca2+]i in the presence of GABA or XHE-III-74A, whereas XHE-III-74EE showed only partial reduction of [Ca2+]i and no inhibition of IL-2 secretion. However, both compounds significantly relaxed pre-contracted tracheal rings ex vivo. Overall, we conclude that the systemic delivery of a α4-subunit-selective GABAAR modulator shows good potential for a novel asthma therapy, however, the pharmacokinetic properties of this class of drug candidates have to be improved to enable better beneficial systemic pharmacodynamic effects.