期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 316, 期 2, 页码 L385-L390出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00356.2018
关键词
asthma; flexiVent; GABA(A); MIDD0301; organ bath; receptor
资金
- National Institutes of Health [HL-140102, HL-122340, HL-118561, GM-065281, MH-096463, DA-031090]
- Louis V. Gerstner Jr. Scholars Program
- Lynde and Harry Bradley-Herzfeld Foundation
- Richard and Ethel Herzfeld Foundation
- University of Wisconsin-Milwaukee Research Foundation
Airway smooth muscle (ASM) cells express GABA A receptors (GABA(A)Rs), and previous reports have demonstrated that GABA(A)R activators relax ASM. However, given the activity of GABA(A)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(A)R 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 three 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 ASM in a number of clinically relevant experimental paradigms, MIDD0301 is a promising drug candidate for bronchoconstrictive diseases, such as asthma.
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