对具有抗抑郁作用的5-HT2A受体激动剂进行定制库对接
Anat Levit Kaplan1, Danielle N Confair2, Kuglae Kim3,4
1Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Nature
|September 28, 2022
概括
研究人员开发了针对血清素受体的新型四胺激动剂. 这些化合物表现出强烈的抗抑郁作用, 没有迷幻效应,
科学领域:
- 医学化学
- 神经科学
- 药物发现
背景情况:
- 对超大化学库的选对联体的发现至关重要.
- 现有的努力往往忽略了尚未研究的化学类型,例如四.
- 四二胺非常适合氨基G蛋白结合受体.
研究的目的:
- 为了研究基于结构的对接, 定制的虚拟图书馆的四.
- 为了确定新型的血清素受体配体,特别是5-HT2A和5-HT2B.
- 探索这些新型化合物的治疗潜力.
主要方法:
- 一个合成提供了多个衍生位点的四胺核.
- 基于结构的对接7500万个分子虚拟图书馆与胺5-HT2A受体模型.
- 合成和测试初始分子,然后基于结构的优化.
- 结晶电子显微镜用于对联受体结合的结构分析.
主要成果:
- 四个合成的分子对5-HT2A或5-HT2B受体表现出低微分子活性.
- 优化化合物 (R) - 69和 (R) - 70对5-HT2A受体具有很高的亲和力 (41nM和110nMEC50).
- 这些激动剂表现出不寻常的信号动力学, 与已知的迷幻化合物不同.
- 大脑的高透性得到证实,使得体内行为测试成为可能.
- 化合物缺乏迷幻活性,但在小鼠模型中表现出强烈的抗抑郁作用.
结论:
- 定制虚拟图书馆可以有效地采样药理相关的化学空间.
- 发现了针对血清素受体的新型四胺激动剂.
- 这些化合物代表一种有前途的新型非迷幻抗抑郁药,
更多相关视频
07:16Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
13.7K
09:09Preparation and Delivery of Protein Microcrystals in Lipidic Cubic Phase for Serial Femtosecond Crystallography
Published on: September 20, 2016
11.6K
相关概念视频
Antidepressant Drugs: MAOIs and Other Agents
314
Atypical antidepressants, including bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone (Serzone), trazodone (Desyrel), and vilazodone (Viibryd), offer unique mechanisms of action. Bupropion weakly inhibits dopamine and norepinephrine reuptake, aiding depression treatment and smoking cessation, with a low risk of sexual dysfunction. Mirtazapine enhances serotonin and norepinephrine neurotransmission, leading to sedation, increased appetite, and weight gain. As a result, it helps treat...
314
G-protein Coupled Receptors
120.9K
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
120.9K
Antidepressant Drugs: Overview
699
Antidepressant drugs are a class of medications primarily used for treating various mood disorders, including major depression, anxiety disorders, and other related conditions. These medicines work by modulating the neurotransmitter balance within the brain, alleviating depressive symptoms. Antidepressants can be broadly categorized into several groups according to their mechanism of action and chemical structure: Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine...
699
Drug-Receptor Interaction: Agonist
2.7K
Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
Agonists can bind to receptors in different ways. Some agonists bind directly to the receptor's active site, mimicking the endogenous...
2.7K
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.5K
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...
2.5K
Antidepressant Drugs: Tricyclics, SSRIs, and SNRIs
530
Tricyclic Antidepressants (TCAs), including Desipramine (Norpramin), Imipramine (Tofranil), Clomipramine (Anafranil), and Amitriptyline (Elavil), inhibit serotonin and norepinephrine reuptake and also block other receptors. They are used for depression, pain conditions, and insomnia. Common adverse effects include anticholinergic effects, sedation, orthostatic hypotension, and weight gain. They have a narrow therapeutic window and so require plasma-level monitoring. Abrupt discontinuation can...
530
