A novel GABAA receptor ligand MIDD0301 with limited blood-brain barrier penetration relaxes airway smooth muscle ex vivo and in vivo. Am J Physiol Lung Cell Mol Physiol 2019 Feb 01;316(2):L385-L390
Date
11/30/2018Pubmed ID
30489155Pubmed Central ID
PMC6397346DOI
10.1152/ajplung.00356.2018Scopus ID
2-s2.0-85060942334 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Airway smooth muscle (ASM) cells express GABA A receptors (GABAARs), and previous reports have demonstrated that GABAAR activators relax ASM. However, given the activity of GABAARs 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 GABAAR 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.
Author List
Yocum GT, Perez-Zoghbi JF, Danielsson J, Kuforiji AS, Zhang Y, Li G, Rashid Roni MS, Kodali R, Stafford DC, Arnold LA, Cook JM, Emala CW SrAuthor
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AnimalsAsthma
Blood-Brain Barrier
GABA Agents
Guinea Pigs
Humans
Ligands
Lung
Male
Muscle, Smooth
Myocytes, Smooth Muscle
Receptors, GABA-A
Trachea