Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments
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- 作者：Gloria S. Forkuo ; Margaret L. Guthrie ; Nina Y. Yuan ; Amanda N. Nieman ; Revathi Kodali ; Rajwana Jahan ; Michael R. Stephen ; Gene T. Yocum ; Marco Treven ; Michael M. Poe ; Guanguan Li ; Olivia B. Yu ; Benjamin D. Hartzler ; Nicolas M. Zahn ; Margot Ernst ; Charles W. Emala ; Douglas C. Stafford ; James M. Cook ; Leggy A. Arnold
- 刊名：Molecular Pharmaceutics
- 出版年：2016
- 出版时间：June 6, 2016
- 年：2016
- 卷：13
- 期：6
- 页码：2026-2038
- 全文大小：800K
- 年卷期：0
- ISSN：1543-8392
文摘
Recent studies have demonstrated that subtype-selective GABAA receptor modulators are able to relax precontracted 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 precontracted 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.