在hCB1上流行的合成大麻素代谢物的结构-活性关系 in vitro 和 in silico动态
Anna Åstrand1, Emiliano Laudadio2, Prince S Gameli3
1Division of Clinical Chemistry and Pharmacology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, SE 581 85 Linköping, Sweden. anna.astrand@liu.se.
Acta pharmacologica Sinica
|November 3, 2025
概括
合成大麻素代谢物被测试在人类大麻素受体1 (hCB) 的活性. 许多代谢物保留了显著的疗效,其中4-基烯衍生物显示出高强度,这表明它们有助于合成大麻素效应.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药用化学 医学化学
- 计算化学计算化学
背景情况:
- 合成大麻素 (SC) 与人类大麻素受体1 (hCB) 相互作用.
- SCs的新陈代谢是广泛的,但其代谢物的hCB1活动在很大程度上是未知的.
- 了解代谢物活性对于评估SC风险至关重要.
研究的目的:
- 为了比较26种合成大麻素受体激素体 (SCRA) 代谢物的hCB1受体活性.
- 为了阐明SC代谢物的结构-活性关系 (SAR).
- 为了将体外发现与in silico模拟相关联.
主要方法:
- 在体外hCB1受体测定 (AequoScreen) 测定26种SCRA代谢物的EC50和Emax.
- 在基分子对接和动力学模拟中,使用一个活跃的hCB受体模型.
- 在生理条件下对代谢物的稳定性评估.
主要成果:
- 炭酸和2-氧醇代谢产物是不活跃的.
- 5-hydroxypentylSCRA代谢物作为部分激动剂起作用.
- 18种代谢物保留了其原始化合物的>70%的疗效.
- 强度在13-3500nm之间,其中4-基丁和4-基醇衍生物是最强的.
- 在的结合能与体外疗效线性相关 (R2 = 0.9457).
结论:
- 对于SC代谢产物,存在明显的结构-活性关系.
- 代谢物,特别是4-基烯衍生物,可能会对合成大麻素的体内作用产生重大影响.
- 分子动力学模拟准确地预测了代谢物活性和结合相互作用.
相关概念视频
Structure-Activity Relationships and Drug Design
1.7K
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
1.7K
Stability of Substituted Cyclohexanes
14.7K
This lesson discusses the stability of substituted cyclohexanes with a focus on energies of various conformers and the effect of 1,3-diaxial interactions.
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
The two chair conformations of cyclohexanes undergo rapid interconversion at room temperature. Both forms have identical energies and stabilities, each comprising equal amounts of the equilibrium mixture. Replacing a hydrogen atom with a functional group makes the two conformations energetically non-equivalent.
For example, in...
14.7K
Mutagenicity and Carcinogenicity
1.9K
Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
1.9K
Disubstituted Cyclohexanes: cis-trans Isomerism
13.9K
Depending upon the different spatial orientation of the substituents, the disubstituted cycloalkanes exhibit two types of stereoisomers. The cis isomers have the substituents on the same side of the ring, whereas the trans isomers have the substituents on the opposite sides. These stereoisomers exhibit different physical properties and cannot be interconverted without breaking the carbon-carbon bonds.
In cyclohexane, the substituents can occupy different positions generating distinct isomers....
In cyclohexane, the substituents can occupy different positions generating distinct isomers....
13.9K
CNS Stimulants: Cocaine, Amphetamines and Cannabinoids
758
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...
758
Prochirality
4.8K
The concept of prochirality leads to the nomenclature of the individual faces of a molecule and plays a crucial role in the enantioselective reaction. It is a concept where two or more achiral molecules react to produce chiral products. A typical process is the reaction of an achiral ketone to generate a chiral alcohol. Here, the achiral reactant reacts with an achiral reducing agent, sodium borohydride, to generate an equimolar mixture of the chiral enantiomers of the product. For example, an...
4.8K

![Technical Aspect of the Automated Synthesis and Real-Time Kinetic Evaluation of [11C]SNAP-7941](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F59557.jpg&w=3840&q=50)
