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

• 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
• 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

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）：需要新的哮喘治疗策略来更好地控制疾病症状和改善生活质量。推荐的一线药物（吸入性皮质类固醇和β-肾上腺素能受体激动剂）并不总是控制症状，疾病可能变得耐药，并可能发生副作用。近年来研究表明，气道平滑肌（ASM）表达α4/α5亚型的γ-氨基丁酸A型受体（GABAAR），相应亚型的选择性激动剂可引起ASM舒张。重要的是，参与炎症的细胞（T淋巴细胞和单核细胞/巨噬细胞谱系的细胞; IC）也已显示表达功能性GABAAR，包括α 4亚型，并且这些细胞的反应性可被GABAAR调节剂抑制。尽管GABAAR信号在哮喘细胞类型中的作用越来越受到重视，但统一和靶向GABAAR反应的策略尚未在治疗上开发或开发。我们研究的长期目标是通过我们的目标来鉴定对受影响的肺组织具有活性和特异性的GABAAR亚基选择性化合物，从而开发更安全和更有效的哮喘药物。我们的中心假设是，ASM和炎症细胞（IC）表达GABAAR，其α亚基的子集有限且重叠，可以用选择性激动剂靶向;从而提供所需的治疗活性（抑制ASM高反应性和炎症），同时避免不良脱靶效应。靶向ASM和IC共同的GABAAR是一种引人注目的哮喘策略，因为ASM细胞可以调节局部免疫反应性，并且炎症介质可以影响ASM反应性。基本原理是靶向肺中的GABAAR将具有药物设计优势，因为：i）预期单一药物物质影响两种细胞类型（ASM和IC）在哮喘病理生理学中起作用; ii）通过避免使用皮质类固醇，预计安全性将得到改善; iii）GABAAR试剂被广泛处方，并具有长期的临床使用历史。我们将通过三个具体目标来实现我们的中心假设：1）通过文库筛选来鉴定在ASM和IC中具有共同活性的GABAAR亚型; 2）建立GABAAR配体在哮喘疾病模型中的功效;以及3）开发具有最佳药理学特性的选择性GABAAR配体。这些目标将产生重大的预期成果。首先，文库筛选将揭示α-亚基GABAAR选择性与肺中药理学功效之间的详细关系。其次，针对α-亚基选择性优化的化合物在动物哮喘模型中将是有效的，证明了药理学概念验证。第三，先导化合物将具有适于安全口服剂量的药物特性。这些结果的积极影响是一种创新的哮喘治疗策略，统一了肺部的GABAAR信号传导，扩展了肺部信号传导机制的知识（和研究工具），并最终改善了患者的护理，与目前的药物相比，新的药物选择具有全新的作用模式，改进了剂型，降低了不良反应的可能性。