Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments.

Autor: Forkuo GS; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Guthrie ML; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Yuan NY; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Nieman AN; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Kodali R; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Jahan R; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Stephen MR; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Yocum GT; Department of Anesthesiology, Columbia University , New York, New York 10032, United States., Treven M; Department of Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria., Poe MM; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Li G; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Yu OB; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Hartzler BD; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Zahn NM; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Ernst M; Department of Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria., Emala CW; Department of Anesthesiology, Columbia University , New York, New York 10032, United States., Stafford DC; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Cook JM; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States., Arnold LA; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Jazyk: angličtina
Zdroj: Molecular pharmaceutics [Mol Pharm] 2016 Jun 06; Vol. 13 (6), pp. 2026-38. Date of Electronic Publication: 2016 May 10.
DOI: 10.1021/acs.molpharmaceut.6b00159
Abstrakt: 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.
Databáze: MEDLINE