Targeting the immune system with subtype-selective GABAA receptor modulator to alleviate asthma symptoms

Inflammation is one of the main characteristics of asthma in addition to mucus metaplasia and airway hyperresponsiveness due to muscle constriction. Therefore, current asthma treatments include corticosteroids, which are associated with many negative side effects1. Recently, small molecule modulators of the γ-aminobutyric acid receptor (GABAAR) have been shown to reduce inflammation and induce airway smooth muscle relaxation2,3. GABAARs are expressed in the neurons to moderate neuronal firing. However other cell types have distinct arrangements of GABAAR subtypes as well, which can be targeted with subtype-selective GABAAR modulators. Our study hypothesizes that compounds targeting GABAARs bearing the α4 subunit will predominantly target airway smooth muscle cells and immune cells. We have developed two subtype-selective GABAAR modulators, Xhe-III-74EE and Xhe-III-74A. Investigations with T cells showed reduced IL-2 levels for treated cells. In addition, both compounds reduced cellular rapid cytoplasmic calcium release upon activation. In vivo studies showed that XHE-III-74A was able to reduce eosinophilia in an ovalbumin sensitized and challenged (Ova S/C) model.