虚拟库对接可用于具有减少副作用的大麻素-1受体激动剂.
Tia A Tummino1,2, Christos Iliopoulos-Tsoutsouvas3, Joao M Braz4
1Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, 94158, USA.
Nature communications
|March 5, 2025
概括
研究人员发现了新的大麻素化学型,它们作为大麻素-1受体 (CB1R) 的激动剂. 这些化合物显示出缓解疼痛的潜力,将止痛作用与常见的大麻素副作用分开.
科学领域:
- 药用化学 医学化学
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 大麻素-1受体 (CB1R) 激动剂正在被用于治疗应用,特别是疼痛管理.
- 识别具有改进副作用概况的新型化学型仍然是一个挑战.
研究的目的:
- 通过虚拟查和基于结构的药物设计,发现新的大麻素-1受体 (CB1R) 激动剂.
- 开发具有良好的治疗窗口的强效和选择性的CB1R激动剂.
主要方法:
- 针对CB1R标的7400万个分子的虚拟选.
- De novo合成和无线电配体竞争测试用于击中优先级.
- 基于结构的优化和冷电子显微镜 (cryo-EM) 用于结构阐明.
- 在雄性小鼠体内止痛试验,评估治疗窗口和副作用.
主要成果:
- 从46种合成化合物中鉴定出9种活性CB1R激动剂,达到20%的命中率.
- 优化了一个化合物到'1350,一个强大的0.95nM的CB1R的全激素.
- 化EM结构证实了"1350"的停靠姿势与CB1R-Gi1的复合.
- 化合物"1350在雄性小鼠中表现出强烈的止痛作用,具有显著的治疗窗口,超过诸如催眠,镇静和催眠等不良影响.
- 与"1350"没有观察到有条件的位置偏好,这表明镇痛效应与奖励性质的分离.
结论:
- 通过虚拟查和基于结构的设计,可以有效地识别新的大麻素化学型.
- 开发的CB1R激动剂'1350表现出强大的止痛活性,具有有前途的安全性.
- 这些发现支持独特的大麻素化学型的潜力,可以将缓解疼痛与不良副作用脱而出,为新的疼痛疗法铺平道路.
相关概念视频
Chemotherapy-Induced Nausea and Vomiting: Cannabinoids
199
Tetrahydrocannabinol (THC) is a phytocannabinoid that primarily interacts with the CB1 receptor, a type of G protein-coupled receptor (GPCR) predominantly in and around the chemoreceptor trigger zone (CTZ) and emetic center. THC also blocks the serotonin receptor activity in the dorsal vagal complex (DVC) by inhibiting serotonin release. THC exerts its anti-emetic effects through these interactions, which are beneficial for patients undergoing chemotherapy.
Two synthetic agonists of THC,...
Two synthetic agonists of THC,...
199
Drug-Receptor Interaction: Agonist
2.3K
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...
2.3K
Drug-Receptor Interactions
4.8K
Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue....
Several parameters, such as the drug's affinity for its receptor and its efficacy, which is its ability to activate the receptor, determine the drug's effect on the tissue....
4.8K
CNS Stimulants: Cocaine, Amphetamines and Cannabinoids
152
CNS stimulants, such as cocaine, amphetamines, and cannabinoids, have varying structures and mechanisms of action that lead to different therapeutic effects and side effects. Cocaine, with its molecular formula C17H21NO4, is a tropane alkaloid and a tertiary amino compound. It has two chemical forms: the hydrochloride salt and the "freebase." The former is in powder form, while the latter involves removing the hydrochloride salt to create a form that can be smoked. Cocaine exerts its...
152
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.1K
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...
2.1K
Drug-Receptor Interaction: Antagonist
2.6K
An antagonist is a drug that binds strongly to a receptor without activating it. An antagonist prevents other molecules, such as neurotransmitters or hormones, from binding to the receptor and triggering a cellular response. Such interaction effectively hinders the normal physiological processes mediated by the receptor, resulting in various pharmacological effects depending on the specific receptor targeted.
Antagonists can be classified as competitive or noncompetitive based on their...
Antagonists can be classified as competitive or noncompetitive based on their...
2.6K


