Development of new drugs for asthma by targeting GABA(A) receptors in the lung

通过靶向肺部 GABA(A) 受体开发治疗哮喘的新药

基本信息

批准号：
8925915
负责人：
James M Cook
金额：
$ 47.17万
依托单位：
UNIVERSITY OF WISCONSIN MILWAUKEE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-10 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925915
关键词：
Adrenal Cortex Hormones Adrenergic Agonists Adverse effects Affect Agonist Animal Model Animals Asthma Binding Biological Assay Breathing Butyric Acids Cell Adhesion Molecules Cell membrane Cells Childhood Chloride Ion Clinical Communities Data Development Disease Disease model Dosage Forms Dose Drug Delivery Systems Drug Design Drug Kinetics Foundations Functional disorder GABA-A Receptor Goals Health Health Care Costs Healthcare Histopathology Human Immune Inflammation Inflammation Mediators Inflammatory Inhalators Interleukin-13 Interleukins Knowledge Lead Libraries Ligands Lung Lymphocyte Membrane Membrane Potentials Minority Mission Modeling Mus Muscle relaxation phase Oral Outcome Ovalbumin Patient Care Pattern Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Population Process Property Public Health Quality of life Recording of previous events Research Resistance Resolution Safety Scheme Sendai virus Signal Transduction Site Smooth Muscle Myocytes Specificity Steroids Structure Structure of parenchyma of lung Symptoms T-Lymphocyte Testing Therapeutic Treatment Efficacy Tumor Necrosis Factor-alpha Work asthmatic base cell type chemokine constriction disorder control dosage gamma-Aminobutyric Acid improved inflammatory marker innovation macrophage member monocyte novel novel therapeutics receptor respiratory smooth muscle response screening small molecule stoichiometry tool

项目摘要

DESCRIPTION (provided by applicant): New therapeutic strategies for asthma are needed to better control disease symptoms and improve quality of life. Recommended first-line drugs (inhaled corticosteroids and ß-adrenergic agonists) do not always control symptoms, disease may become resistant, and side effects can occur. Recently, it was shown that airway smooth muscle (ASM) express γ-amino butyric acid type A receptors (GABAAR) of the α4/α5 subtype and corresponding subtype selective agonists cause ASM relaxation. Importantly, cells that participate in inflammation (T-lymphocytes and cells of monocyte/macrophage lineage; IC) have also been shown to express functional GABAAR, including the a4 subtype, and reactivity of these cells can be suppressed by GABAAR modulating agents. Despite the growing appreciation of GABAAR signaling in asthma cell types, a strategy that unifies and targets GABAAR responses has not been developed or exploited therapeutically. The long-term goal of our research is to develop safer and more effective asthma drugs by way of our objective to identify GABAAR subunit selective compounds with activity and specificity for affected lung tissues. Our central hypothesis is that ASM and inflammatory cells (IC) express GABAARs with a limited and overlapping subset of α-subunits that can be targeted with selective agonists; thus providing desired therapeutic activity (suppression of both ASM hyperresponsiveness and inflammation) while avoiding adverse off-target effects. Targeting GABAAR common to both ASM and IC is a compelling asthma strategy because ASM cells can modulate local immune reactivity and inflammatory mediators can influence ASM responsiveness The rationale is that targeting GABAAR in the lung would have drug design advantages because: i) a single drug substance is expected to affect two cell types (ASM and IC) that conspire in asthma pathophysiology; ii) safety is expected to be improved by avoiding corticosteroid use, and; iii) GABAAR agents are prescribed extensively and have a long history of clinical use. We will pursue our central hypothesis by way of three Specific Aims: 1) identify GABAAR subtypes by library screening that have common activity in ASM and IC; 2) establish efficacy of GABAAR ligands in asthma disease models; and, 3) develop selective GABAAR ligands with optimal pharmacological properties. These Aims will yield significant expected outcomes. First, library screening will reveal a detailed relationship between α-subunit GABAAR selectivity and pharmacological efficacy in the lung. Second, compounds optimized for α-subunit selectivity will be efficacious in animal asthma models demonstrating pharmacological proof-of-concept. Third, lead compounds will have pharmaceutical properties suitable for safe oral dosage. The positive impacts of these outcomes are an innovative therapeutic strategy for asthma that unifies GABAAR signaling in the lung, expanded knowledge of (and tools to study) lung signaling mechanisms, and ultimately improved patient care from a new drug choice with a fundamentally novel mode of action, improved dosage form, and reduced potential for adverse effects compared to current drugs.

描述（由申请人提供）：需要哮喘的新治疗策略来更好地控制疾病症状并改善推荐的一线药物（吸入的皮质类固醇 - 肾上腺素能激动剂）并不总是控制症状效果可能表明，气道平滑肌（ASM）表达γ-氨基酸丁酸A型受体（GABAAR）α5亚型，并且相关的亚型选择性激动剂可获得炎症。尽管哮喘细胞类型中的Gabaar信号越来越多，但Gabaar调节剂的表达功能性GABAAR类型和抑制剂的反应性尚未开发或开发出更多的治疗方法。通过客观鉴定具有活性的GABAAR亚基选择性化合物的药物，我们的中心假设特异性。脱靶效应。通过避免使用皮质类固醇激素的使用；）在哮喘疾病模型中建立了Gabaar配体的功效； 3）具有最佳药理学特性的选择性Gabaar配体。 NG。在动物哮喘模型中优化了α-亚基的选择性，证明了药理学的概念与当前药物相比，肺中的GABAAR信号传导，扩展了具有基本的新型作用方式，改善剂型的新型作用方式，与当前药物相比，具有基本的新型作用方式，改善剂型的剂型以及对敌人效应的潜力降低的知识。