Our goal to develop a novel oral drug to alleviate the hallmark asthma symptoms of airway hyperresponsiveness and lung inflammation has led to the synthesis of positive allosteric modulators for specific GABAA receptors (GABAARs). This approach is based on recent findings that lung cell types involved in asthma pathology (airway smooth muscle (ASM) and immune/inflammatory cells) express discrete GABAARs, expression of which is well known in CNS. Starting with positive modulators designed for CNS disorders, such as anxiety or schizophrenia, we engineered new molecules that retain GABAAR selectivity but do not cross the blood brain barrier, and distribute to the lung to relax constricted ASM and reduce asthma inflammation. Compounds with desired pharmacodynamic performance were optimized further for oral availability, metabolic stability, pharmacokinetics (including extended plasma half-life and good lung exposure), and limited CNS distribution. Immunohistochemistry was used to verify the expression of GABAARs on lung cell types, including white blood cells, and electrophysiology to demonstrate functional GABAAR activity in these cell. Finally, we present flow cytometry and immunochemistry data that show anti-inflammatory leucocyte population and cytokine effects of GABAAR modulators in the asthmatic mice. Taken together, these results demonstrate for the first time the feasibility of targeting asthma with an orally available GABAAR ligand.

Development of new therapies for asthma based on compounds that specifically target GABAA receptors in the lung

253rd National Meeting (2017)

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