基于μ-阿片类受体的比托皮配体的结构设计
Abdelfattah Faouzi1, Haoqing Wang2, Saheem A Zaidi3
1Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University School of Medicine, St Louis, MO, USA.
Nature
|November 30, 2022
概括
研究人员设计了针对片受体 (μOR) 离子位点的新型芬太尼衍生物,以制造更安全的止痛药. 这些化合物减少了副作用,为止痛药开发提供了有前途的新途径.
科学领域:
- 药理学
- 结构生物学
- 医学化学
背景情况:
- 像芬太尼这样的类受体 (μOR) 激动剂是有效的止痛药,但由于包括过量服用在内的不良影响,它们对公众健康构成重大风险.
- 在μOR和其他A类G蛋白合受体 (GPCRs) 中保存的离子结合位是开发更安全的治疗方法的潜在目标.
研究的目的:
- 设计和描述针对μOR离子结合部位的新型比托衍生物.
- 通过调节受体信号通路,研究这些配体产生具有改善安全性特征的止痛药的潜力.
主要方法:
- 用瓜尼迪诺组功能化的双芬太尼衍生物的合成.
- 用冷电子显微镜测定μOR连接体的结构.
- 在体外测试以评估G蛋白和阿斯特林信号的有效性.
- 在小鼠体内进行研究,以评估抗受和不良反应.
主要成果:
- 与瓜尼迪诺基团功能化的比托基连接物有效地向μOR离子位点,形成与Asp2.50的关键相互作用.
- 两种化合物,C5和C6瓜诺,在Gi亚型中表现出纳米强度和高效率,其阿斯特林招募率降低.
- 在小鼠中,C6瓜诺表现出测试的μOR激动剂中最低的Gz疗效,并表现出μOR依赖的抗受体与减弱的不良反应.
结论:
- 通过专门设计的比托基连接剂向μOR离子结合部位,可以获得具有更好的安全性概况的止痛药.
- 不同G蛋白亚型和阿雷斯的调节效果和功能选择性可以通过比托普连接体设计来实现.
- 这种方法通过使用GPCR离子口袋,为开发更安全的疼痛治疗提供了有希望的策略.
相关概念视频
01:22Opioid Receptors: Overview
1.5K
Opioid receptors, including the mu (μ, MOR), delta (δ, DOR), and kappa (κ, KOR) types, belong to the rhodopsin family of G protein-coupled receptors. These receptors are located throughout the central and peripheral nervous systems and in non-neuronal tissues such as macrophages and astrocytes. Opioid receptor ligands can be categorized into agonists or antagonists. Highly selective agonists include [d-Ala2, MePhe4, Gly(ol)5]-enkephalin or DAMGO for MOR, [D-Pen2,...
1.5K
01:25Analgesia and Pain Management
726
Pain is critical to various clinical pathologies, provoking an urgent need for effective management. Pain, whether acute or chronic, is a complex neurochemical process. Its alleviation depends on the type, with nonopioid analgesics effective for mild to moderate pain, such as musculoskeletal or inflammatory pain, while neuropathic pain responds best to anticonvulsants, tricyclic antidepressants, or serotonin/norepinephrine reuptake inhibitors. For severe acute or chronic pain, opioids may be...
726
02:40Ligand Binding Sites
7.8K
7.8K
01:29The Two-State Receptor Model
2.1K
The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
The binding affinity of a drug determines its interaction with...
2.1K
01:15Opioid Analgesics: Synthetic and Semisynthetic Opioids
377
Synthetic and semisynthetic opioids are pivotal in pain management and tackling opioid addiction. Semisynthetic opioids, including morphinans (morphine derivatives), oxycodone, oxymorphone, hydrocodone, and hydromorphone, have improved pharmacokinetic profiles compared to morphine. Additionally, heroin and 6-MAM (6-Monoacetylmorphine) show better CNS penetration than morphine due to heightened lipid solubility. Hydromorphone, a potent opioid, undergoes hepatic metabolism to form the active...
377
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.4K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
2.4K