Development of GABA_A Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

Recent studies have demonstrated that subtype-selective GABA_A receptor modulators are able to relax precontracted human airway smooth muscle <i>ex vivo</i> and reduce airway hyper-responsiveness in mice upon aerosol administration. Our goal in this study was to investigate systemic administration of subtype-selective GABA_A receptor modulators to alleviate bronchoconstriction in a mouse model of asthma. Expression of GABA_A receptor subunits was identified in mouse lungs, and the effects of α4-subunit-selective GABA_AR 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 <i>ex vivo</i>. Overall, we conclude that the systemic delivery of a α4-subunit-selective GABA_AR 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