Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments.
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.
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Gloria S
GS
Forkuo
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Margaret L
ML
Guthrie
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Nina Y
NY
Yuan
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Amanda N
AN
Nieman
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Revathi
R
Kodali
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Rajwana
R
Jahan
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Michael R
MR
Stephen
Department of Anesthesiology, Columbia University , New York, New York 10032, United States.
Gene T
GT
Yocum
Department of Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria.
Marco
M
Treven
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Michael M
MM
Poe
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Guanguan
G
Li
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Olivia B
OB
Yu
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Benjamin D
BD
Hartzler
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Nicolas M
NM
Zahn
Department of Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria.
Margot
M
Ernst
Department of Anesthesiology, Columbia University , New York, New York 10032, United States.
Charles W
CW
Emala
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Douglas C
DC
Stafford
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
James M
JM
Cook
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
Leggy A
LA
Arnold
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage; D011963:Receptors, GABA-A / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis
D007376:Interleukin-2; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D010047:Ovalbumin
GABA; GABAA receptor; XHE-III-74A; XHE-III-74EE; airway smooth muscle; asthma; eosinophilia; inflammation