Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators. Mol Pharm 2017 Jun 05;14(6):2088-2098
Date
04/26/2017Pubmed ID
28440659Pubmed Central ID
PMC5497587DOI
10.1021/acs.molpharmaceut.7b00183Scopus ID
2-s2.0-85020166818 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
We describe pharmacokinetic and pharmacodynamic properties of two novel oral drug candidates for asthma. Phenolic α4β3γ2 GABAAR selective compound 1 and acidic α5β3γ2 selective GABAAR 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 GABAARs. 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.
Author List
Forkuo GS, Nieman AN, Yuan NY, Kodali R, Yu OB, Zahn NM, Jahan R, Li G, Stephen MR, Guthrie ML, Poe MM, Hartzler BD, Harris TW, Yocum GT, Emala CW, Steeber DA, Stafford DC, Cook JM, Arnold LAAuthors
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeJames M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee
MESH terms used to index this publication - Major topics in bold
AnimalsAsthma
Bronchoalveolar Lavage Fluid
Disease Models, Animal
Eosinophils
Flow Cytometry
Humans
Lung
Male
Mice
Mice, Inbred BALB C
Ovalbumin
Receptors, GABA
Respiratory Hypersensitivity
Swine
