New Oral Treatments for Asthma through Tissue-Specific Modulation of the GABAA Receptor

Abstract

This study addresses the unmet need for an oral, safe, non-steroidal asthma treatment. The hypothesis is that GABAARs in airway smooth muscle (ASM) and inflammatory cells can be targeted by subtype-selective GABAAR modulators to tissue-selectively induce ASM relaxation and immunosuppression. New drug candidates were characterized by electrophysiology and microsome, S9, and blood plasma stability assays. Pharmacokinetic studies in mice are used to identify in vivo stability and distribution. Murine pharmacodynamic models are used to quantify sensorimotor effects (rotarod), disease specific airway hyperresponsiveness, airway mucus production, and airway eosinophilia. ASM muscle relaxation was tested in ex vivo lung tissue. The immune modulatory effect of subtype-selective GABAAR ligands was evaluated by flow cytometry. A α5 subtype-selective GABAAR ligand showed excellent PK when given orally. The compound did not cross the BBB, thus no sensorimotor effects were observed. The compound inhibited eosinophilia and reduced the number of inflammatory cells. Significant muscle relaxation was observed ex vivo in trachea rings and reduced airway hyperresponsiveness was observed in mice. Importantly, this is the first oral treatment for asthma specifically targeting muscle relaxation and inflammation. In addition, a novel α4 subtype-selective GABAAR ligand was identified with equally excellent stability in vitro and in vivo. Reduced airway hyperresponsiveness was observed at low concentrations of methacholine. The anti-inflammatory properties were significant but immune cell populations were regulated differently. α4 and α5-selective GABAAR modulators have a great potential as novel orally active drug candidates for asthma to alleviate symptoms of airway hyperresponsiveness mediated by ASM constriction, hypereosinophilia, and inflammation.