Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABA_A Receptor...

We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic α₄β₃γ₂ GABA_AR selective compound 1 and acidic α₅β₃γ₂ selective GABA_AR positive allosteric modulator compound 2 relaxed airway smooth muscle ex vivo and attenuated airway hyperresponsiveness (AHR) in a murine model of asthma. Importantly, compound 2 relaxed acetylcholine contracted human tracheal airway smooth muscle strips. Oral treatment of compounds 1 and 2 decreased eosinophils in bronchoalveolar lavage fluid in ovalbumin sensitized and challenged mice, thus exhibiting anti-inflammatory properties. Additionally, compound 1 reduced the number of lung CD4⁺ T lymphocytes and directly modulated their transmembrane currents by acting on GABA_ARs. Excellent pharmacokinetic properties were observed, including long plasma half-life (up to 15 h), oral availability, and extremely low brain distribution. In conclusion, we report the selective targeting of GABA_ARs expressed outside the brain and demonstrate reduction of AHR and airway inflammation with two novel orally available GABA_AR ligands.