A Novel GABA A Receptor Ligand MIDD0301 with Limited Blood-Brain Barrier Penetration Relaxes Airway Smooth Muscle Ex Vivo and In Vivo.

Airway smooth muscle cells express GABAA receptors, and previous reports have demonstrated that GABAA receptor activators relax airway smooth muscle. However, given the activity of GABAA receptors in central nervous system inhibitory neurotransmission, concern exists that these activators may lead to undesirable sedation. MIDD0301 is a novel imidazobenzodiazepine and positive allosteric modulator of the GABAA receptor with limited brain distribution, thus eliminating the potential for sedation. Here we demonstrate that MIDD0301 relaxes histamine-contracted guinea pig (p<0.05, n=6-9) and human (p<0.05, n=6-10) tracheal smooth muscle ex vivo in organ bath experiments, dilates mouse peripheral airways ex vivo in precision-cut lung slice experiments (p<0.001, n=16 airways from 3 mice), and alleviates bronchoconstriction in vivo in mice as assessed by the forced-oscillation technique (p<0.05, n=6 mice). Only trace concentrations of the compound were detected in the brains of mice after inhalation of nebulized 5 mM MIDD0301. Given its favorable pharmacokinetic properties and demonstrated ability to relax airway smooth muscle in a number of clinically relevant experimental paradigms, MIDD0301 is a promising drug candidate for bronchoconstrictive diseases like asthma.