δ-阿片受体(DOR)选择性激动剂knt -127的结构-信号关系——第二部分:喹啉环修饰增强g蛋白信号传导和减少β-阻滞蛋白募集。

IF 1.5 4区 医学 Q4 CHEMISTRY, MEDICINAL
Keita Kajino, Tomoya Sugai, Tomoya Kakumoto, Ryoji Kise, Riko Suzuki, Akihisa Tokuda, Yuki Sekiya, Risako Katamoto, Noriki Kutsumura, Yasuyuki Nagumo, Takatsugu Hirokawa, Asuka Inoue, Tsuyoshi Saitoh
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引用次数: 0

摘要

δ-阿片受体(DOR)与μ-阿片受体(MOR)相比,具有较低的不良反应风险,因此作为开发更安全的镇痛药的治疗靶点,δ-阿片受体(DOR)继续受到关注。基于我们之前对KNT-127(一种带有吗啡肽支架的dor选择性激动剂)的研究结果,本研究进一步探讨了喹啉环修饰与gi蛋白激活的信号偏好之间的结构-信号关系,同时最小化β-arrestin-2的募集。我们的研究结果强调了5'位置在调节信号偏倚中的关键作用。大体积的疏水取代基,如异丙氧基和环己氧基,可以有效地减少β-arrestin-2的募集,而不会影响DOR的结合亲和力或gi蛋白的激活。分子对接和分子动力学模拟提供了机制见解,表明这些修饰改变了配体与V2816.55-W2846.58-L3007.35子口袋的相互作用,从而选择性地支持gi蛋白信号传导。这些见解阐明了DOR激动剂信号偏倚的关键相互作用,为DOR靶向治疗的设计提供了一个新的框架,并改善了治疗方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structure-Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127-Part II: Quinoline Ring Modifications for Enhanced G-Protein Signaling and Reduced β-Arrestin Recruitment.

The δ-opioid receptor (DOR) continues to attract attention as a therapeutic target for the development of safer analgesics due to its ability to mediate pain relief with a lower risk of adverse effects compared to the μ-opioid receptor (MOR). Building upon our previous findings on KNT-127, a DOR-selective agonist with a morphinan scaffold, this study further explores the structure-signal relationships between quinoline ring modifications and the signaling bias toward Gi-protein activation while minimizing β-arrestin-2 recruitment. Our findings highlight the critical role of the 5'-position in modulating signaling bias. Bulky hydrophobic substituents, such as isopropoxy and cyclohexanoxy groups, effectively reduce β-arrestin-2 recruitment without compromising DOR binding affinity or Gi-protein activation. Molecular-docking and molecular dynamics simulations provided mechanistic insights, showing that these modifications change ligand interactions with the V2816.55-W2846.58-L3007.35 sub-pocket, thus selectively favoring Gi-protein signaling. These insights clarify the key interactions for the signaling bias in DOR agonists, offering a new framework for the design of DOR-targeted therapies with an improved therapeutic profile.

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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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