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Mol Pharm
2016 Jun 06;136:2026-38. doi: 10.1021/acs.molpharmaceut.6b00159.
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Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments.
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
.
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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 [Ca(2+)]i in the presence of GABA or XHE-III-74A, whereas XHE-III-74EE showed only partial reduction of [Ca(2+)]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.
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