A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABAA Receptors in the Lung
| Autor: | Gloria S. Forkuo, James M. Cook, Gene T. Yocum, Revathi Kodali, Leggy A. Arnold, Rajwana Jahan, Michael Rajesh Stephen, Margaret L. Guthrie, Douglas A. Steeber, Charles W. Emala, Douglas C. Stafford, Olivia B. Yu, Guanguan Li, Nicolas M Zahn, Ted William Harris, Janet L. Fisher, Amanda N. Nieman, M S Rashid Roni |
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| Rok vydání: | 2018 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male 0301 basic medicine Ovalbumin medicine.medical_treatment Guinea Pigs Pharmaceutical Science Inflammation Pharmacology Ligands Article Guinea pig Mice 03 medical and health sciences 0302 clinical medicine Drug Discovery Respiratory Hypersensitivity medicine Animals Receptor Lung Mice Inbred BALB C medicine.diagnostic_test biology Chemistry GABAA receptor Macrophages Brain Muscle Smooth respiratory system Receptors GABA-A Constriction Asthma Eosinophils 030104 developmental biology Cytokine Bronchoalveolar lavage biology.protein Cytokines Molecular Medicine Female medicine.symptom Bronchoalveolar Lavage Fluid 030217 neurology & neurosurgery Ex vivo |
| Zdroj: | Molecular Pharmaceutics. 15:1766-1777 |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | We describe lead compound MIDD0301 for the oral treatment of asthma based on previously developed positive allosteric α(5)β(3)γ(2) selective GABA(A) receptor (GABA(A)R) ligands. MIDD0301 relaxed airway smooth muscle at single micromolar concentrations as demonstrated with ex vivo guinea pig tracheal rings. MIDD0301 also attenuated airway hyperresponsiveness (AHR) in an ovalbumin murine model of asthma by oral administration. Reduced numbers of eosinophils and macrophages were observed in mouse broncho-alveolar lavage fluid without changing mucous metaplasia. Importantly, lung cytokine expression of IL-17A, IL-4, and TNF-α were reduced for MIDD0301 treated mice without changing anti-inflammatory cytokine IL-10 levels. Automated patch clamp confirmed amplification of GABA induced current mediated by α(1-3,5)β(3)γ(2) GABA(A)Rs in the presence of MIDD0301. Pharmacodynamically, transmembrane currents of ex vivo CD4(+) T cells from asthmatic mice were potentiated by MIDD0301 in the presence of GABA. The number of CD4(+) T cell observed in the lung of MIDD0301 treated mice were reduced by an oral treatment of 20 mg/kg b.i.d. for 5 days. A half-life of almost 14 hours was demonstrated by pharmacokinetic studies (PK) with no adverse CNS effects when treated mice were subjected to sensorimotor studies using the rotarod. PK studies also confirmed very low brain distribution. In conclusion, MIDD0301 represents a safe and improved oral asthma drug candidate that relaxes airway smooth muscle and attenuates inflammation in the lung leading to a reduction of AHR at a dosage lower than earlier reported GABA(A)R ligands. |
| Databáze: | OpenAIRE |
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