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Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments. Mol Pharm 2016 06 06;13(6):2026-38

Date

04/28/2016

Pubmed ID

27120014

Pubmed Central ID

PMC4899155

DOI

10.1021/acs.molpharmaceut.6b00159

Scopus ID

2-s2.0-84973661516   17 Citations

Abstract

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.

Author List

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

Authors

Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - Milwaukee
James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee




MESH terms used to index this publication - Major topics in bold

Animals
Asthma
Benzodiazepines
Cell Line, Tumor
Disease Models, Animal
Female
Guinea Pigs
Humans
Interleukin-2
Jurkat Cells
Male
Mice
Mice, Inbred BALB C
Muscle, Smooth
Ovalbumin
Receptors, GABA-A
Respiratory System
T-Lymphocytes
Xenopus laevis