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However, given the activity of GABA<jats:sub>A<\/jats:sub>Rs 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 GABA<jats:sub>A<\/jats:sub>R with limited brain distribution, thus eliminating the potential for sedation. Here, we demonstrate that MIDD0301 relaxes histamine-contracted guinea pig ( P &lt; 0.05, n = 6\u20139) and human ( P &lt; 0.05, n = 6\u201310) tracheal smooth muscle ex vivo in organ bath experiments, dilates mouse peripheral airways ex vivo in precision-cut lung-slice experiments ( P &lt; 0.001, n = 16 airways from three mice), and alleviates bronchoconstriction in vivo in mice, as assessed by the forced-oscillation technique ( P &lt; 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 ASM in a number of clinically relevant experimental paradigms, MIDD0301 is a promising drug candidate for bronchoconstrictive diseases, such as asthma. <\/jats:p>","DOI":"10.1152\/ajplung.00356.2018","type":"journal-article","created":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T09:41:35Z","timestamp":1543484495000},"page":"L385-L390","source":"Crossref","is-referenced-by-count":17,"title":["A novel GABA<sub>A<\/sub> receptor ligand MIDD0301 with limited blood-brain barrier penetration relaxes airway smooth muscle ex vivo and in vivo"],"prefix":"10.1152","volume":"316","author":[{"given":"Gene T.","family":"Yocum","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose F.","family":"Perez-Zoghbi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Danielsson","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aisha S.","family":"Kuforiji","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanguan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, Wisconsin"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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