Structure-Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127-Part I: Impact of the Morphinan Skeleton on the G-Protein-Biased DOR Agonism.

IF 1.5 4区 医学 Q4 CHEMISTRY, MEDICINAL
Keita Kajino, Tomoya Sugai, Ryoji Kise, Riko Suzuki, Akihisa Tokuda, Yuki Sekiya, Tomoya Kakumoto, Risako Katamoto, Noriki Kutsumura, Yasuyuki Nagumo, Asuka Inoue, Tsuyoshi Saitoh
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Abstract

The δ-opioid receptor (DOR) is a promising target for developing novel analgesics due to its lower risk of causing side effects compared to the μ-opioid receptor (MOR), which is commonly associated with dependence, respiratory depression, and other adverse effects. KNT-127, a DOR-selective agonist with a morphinan skeleton, offers analgesic and antidepressant benefits without inducing convulsions at therapeutic doses, unlike the conventional DOR agonist SNC80. While previous studies have suggested that KNT-127 exhibits reduced β-arrestin recruitment, a signaling pathway implicated in adverse opioid effects, the ligand structural basis for this biased signaling remains unclear. In this study, we explored the structure-signal relationships of KNT-127, focusing on its quinoline moiety, which is known to serve as an address domain responsible for DOR selectivity. Modifying the quinoline moiety by removing the aromatic rings reduced DOR selectivity and potency in relation to G-protein activation while diminishing both the potency and efficacy of β-arrestin recruitment. These results suggest that the morphinan skeleton is critical for reduced β-arrestin recruitment, while the quinoline moiety differentially modulates G-protein activation and β-arrestin recruitment. Together, our study expands the message-address concept, previously limited to receptor selectivity, by providing structural insights into the G-protein-biased agonism of DOR agonists, thereby guiding the design of safer DOR-targeting therapeutics.

δ-阿片受体(DOR)选择性激动剂knt -127的结构-信号关系——第一部分:Morphinan骨架对g蛋白偏倚DOR激动作用的影响
与μ-阿片受体(MOR)相比,δ-阿片受体(DOR)具有较低的副作用风险,是开发新型镇痛药的一个有希望的靶点,而μ-阿片受体(MOR)通常与依赖、呼吸抑制等不良反应有关。与传统DOR激动剂SNC80不同,具有吗啡酮骨架的DOR选择性激动剂KNT-127在治疗剂量下具有镇痛和抗抑郁作用,而不会引起惊厥。虽然先前的研究表明,KNT-127表现出β-阻滞蛋白募集减少,这是一种与阿片不良反应有关的信号通路,但这种偏倚信号的配体结构基础尚不清楚。在本研究中,我们探索了KNT-127的结构-信号关系,重点关注其喹啉部分,该部分被认为是负责DOR选择性的地址域。通过去除芳环来修饰喹啉部分降低了DOR的选择性和与g蛋白激活相关的效力,同时降低了β-阻滞蛋白募集的效力和功效。这些结果表明,morphinan骨架对减少β-阻滞蛋白募集至关重要,而喹啉部分则对g蛋白激活和β-阻滞蛋白募集有差异调节。总之,我们的研究通过提供DOR激动剂的g蛋白偏向激动作用的结构见解,扩展了以前仅限于受体选择性的信息地址概念,从而指导设计更安全的DOR靶向治疗方法。
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来源期刊
CiteScore
3.20
自引率
5.90%
发文量
132
审稿时长
1.7 months
期刊介绍: The CPB covers various chemical topics in the pharmaceutical and health sciences fields dealing with biologically active compounds, natural products, and medicines, while BPB deals with a wide range of biological topics in the pharmaceutical and health sciences fields including scientific research from basic to clinical studies. For details of their respective scopes, please refer to the submission topic categories below. Topics: Organic chemistry In silico science Inorganic chemistry Pharmacognosy Health statistics Forensic science Biochemistry Pharmacology Pharmaceutical care and science Medicinal chemistry Analytical chemistry Physical pharmacy Natural product chemistry Toxicology Environmental science Molecular and cellular biology Biopharmacy and pharmacokinetics Pharmaceutical education Chemical biology Physical chemistry Pharmaceutical engineering Epidemiology Hygiene Regulatory science Immunology and microbiology Clinical pharmacy Miscellaneous.
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