Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators

We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic alpha(4)beta(3)gamma(2) GABA(A)R selective compound 1 and acidic alpha(5)beta(3)gamma(2) selective GABA(A)R 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(A)Rs. 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 GABAARs expressed, outside the brain and, demonstrate reduction of AHR and airway inflammation with two novel orally available GABAAR ligands.