Biased Orthosteric Agonism and Allosteric Modulation: Emerging Strategies for Developing New Class of β-Agonists for Obstructive Airway Diseases.

IF 5.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sushrut D Shah, Deepak A Deshpande
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引用次数: 0

Abstract

The obstructive lung diseases (OLDs) asthma and chronic obstructive pulmonary disease are characterized by bronchoconstriction and difficulty in breathing. Agonists of β2-adrenergic receptors (β-agonists) are the most commonly used bronchodilators. To enhance their clinical effectiveness, extensive attempts have been made to improve their receptor subtype selectivity and duration of action, resulting in the development of long- and ultra-long-acting β-agonists. While these drugs effectively alleviate OLD symptoms, concerns have arisen regarding their safety, reduced therapeutic benefits, and the potential for worsening asthma symptoms. These concerns have led to restrictions on β-agonist use. Recent advances in G protein-coupled receptor (GPCR) pharmacology and biochemistry have introduced new concepts in drug development, such as "biased agonism" and "allosteric modulation." These advancements stem from a deeper understanding of the molecular interactions between β2-adrenergic receptors (β2AR) and various intracellular proteins (e.g., heterotrimeric G-proteins and β-arrestins), which induce a diverse array of functional changes in airway cells. Biased agonism and allosteric modulation offer new avenues for developing the next generation of β-agonists with improved pharmacological properties. This review explores the application of these concepts in developing new β2AR ligands, including orthosteric and allosteric ligands, that selectively enhance therapeutically beneficial Gs signaling while minimizing harmful β-arrestin-mediated effects in airway cells.

偏倚正构激动剂和变构调节:开发新型β激动剂治疗阻塞性气道疾病的新策略。
阻塞性肺疾病(OLDs)哮喘和慢性阻塞性肺疾病以支气管收缩和呼吸困难为特征。β2肾上腺素能受体激动剂(β激动剂)是最常用的支气管扩张剂。为了提高它们的临床疗效,人们进行了广泛的尝试,以提高它们的受体亚型选择性和作用时间,从而开发了长效和超长效β激动剂。虽然这些药物有效地缓解了OLD症状,但人们对其安全性、治疗效果降低以及哮喘症状恶化的可能性感到担忧。这些担忧导致了对β激动剂使用的限制。近年来在G蛋白偶联受体(GPCR)药理学和生物化学方面的进展为药物开发引入了新的概念,如“偏倚激动作用”和“变构调节”。这些进展源于对β2-肾上腺素能受体(β2AR)和各种细胞内蛋白(如异源三聚体g蛋白和β-阻滞蛋白)之间分子相互作用的更深入理解,这些相互作用诱导气道细胞的各种功能变化。偏倚激动剂和变构调节为开发具有改进药理特性的下一代β激动剂提供了新的途径。这篇综述探讨了这些概念在开发新的β2AR配体中的应用,包括正构配体和变构配体,这些配体选择性地增强治疗上有益的Gs信号,同时最大限度地减少气道细胞中β-抑制蛋白介导的有害作用。
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来源期刊
CiteScore
11.20
自引率
3.10%
发文量
370
审稿时长
3-8 weeks
期刊介绍: The American Journal of Respiratory Cell and Molecular Biology publishes papers that report significant and original observations in the area of pulmonary biology. The focus of the Journal includes, but is not limited to, cellular, biochemical, molecular, developmental, genetic, and immunologic studies of lung cells and molecules.
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