Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators
| Autor: | Michael M. Poe, James M. Cook, Douglas C. Stafford, Leggy A. Arnold, Amanda N. Nieman, Nicolas M Zahn, Michael Rajesh Stephen, Ted William Harris, Guanguan Li, Revathi Kodali, Gene T. Yocum, Rajwana Jahan, Charles W. Emala, Benjamin D. Hartzler, Olivia B. Yu, Margaret L. Guthrie, Nina Y. Yuan, Douglas A. Steeber, Gloria S. Forkuo |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Allosteric modulator Ovalbumin Swine Pharmaceutical Science Pharmacology Article Mice 03 medical and health sciences Receptors GABA Pharmacokinetics Drug Discovery Respiratory Hypersensitivity medicine Animals Humans Distribution (pharmacology) Lung Mice Inbred BALB C medicine.diagnostic_test biology GABAA receptor Chemistry respiratory system Flow Cytometry Asthma respiratory tract diseases Eosinophils Disease Models Animal 030104 developmental biology Bronchoalveolar lavage biology.protein Molecular Medicine Bronchoalveolar Lavage Fluid Ex vivo Acetylcholine medicine.drug |
| Zdroj: | Molecular Pharmaceutics. 14:2088-2098 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.7b00183 |
| Popis: | 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 compound 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 hours), 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. |
| Databáze: | OpenAIRE |
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