相关实验视频
Updated: Jun 7, 2025
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
05:15
Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
6.8K
螺旋环 σ1受体连接体与四水烯基支架的合成和结构亲和关系
Tobias Winge1, Dirk Schepmann1, Judith Schmidt1
1Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Corrensstraße 48, D-48149, Münster, Germany.
European journal of medicinal chemistry
|November 15, 2024
概括
研究人员合成了新的螺旋环西格玛-1受体 (σ1R) 配体. 化合物5i显示出高亲和力和选择性,而阿泽衍生物显示出增强的σ1R结合,表明药物开发的潜力.
科学领域:
- 药用化学 医学化学
- 神经药理学神经药理学
- 药物发现 药物发现 药物发现
背景情况:
- 西格玛-1受体 (σ1R) 与神经退行性疾病,神经精神疾病和癌症有关.
- 瘤中σ1R的过度表达使其成为治疗干预的重要目标.
- 螺旋环化合物被探索为它们作为σ1R配体的潜力.
研究的目的:
- 为了合成和评估新型的螺旋环 σ1R 配体与不同的替代剂.
- 评估合成化合物的亲和力,选择性,脂性和代谢稳定性.
- 为了研究这些连接体的结构-活性关系.
主要方法:
- 合成带有多种4位和9位替代物的螺旋环 σ1R 配体.
- 测量 σ1R 亲和力 (Ki) 和对相关目标 (例如, σ2 受体) 的选择性.
- 确定脂友性 (logD7.4) 和计算脂友性联体效率 (LLE).
- 使用小鼠肝脏显微体评估血蛋白结合和代谢稳定性.
主要成果:
- 化合物5i,一种 (皮里丁-3-) 甲基衍生物,表现出高 σ1R 亲和力 (Ki = 3.9 nM),超过 250 倍的选择性和 5.8.8 的 LLE.
- 化合物5i显示89%的血蛋白结合和83%的代谢稳定性.
- 将piperidine环扩大到azepane支架显著提高了σ1R亲和力 (Ki值降至0.42nM) 和选择性 (比σ2受体高达150倍).
结论:
- 带有特定替代物的螺旋环联体表现出强有力的和选择性的σ1R结合.
- 脂性和结构修改,如环扩张,对于优化连接体特性至关重要.
- 像5i和阿泽衍生物这样的有前途的候选物值得进一步研究以针对s1R的治疗应用.
相关概念视频
Diels–Alder Reaction Forming Bridged Bicyclic Products: Stereochemistry
4.6K
Diels–Alder reactions between cyclic dienes locked in an s-cis configuration and dienophiles yield bridged bicyclic products.
4.6K
Aromatic Hydrocarbon Cations: Structural Overview
2.8K
Cycloheptatriene is a neutral monocyclic unsaturated hydrocarbon that consists of an odd number of carbon atoms and an intervening sp3 carbon in the ring. The three double bonds in the ring correspond to 6 π electrons, which is a Huckel number, and therefore satisfies the criteria of 4n + 2 π electrons. However, the intervening sp3 carbon disrupts the continuous overlap of p orbitals. As a result, cycloheptatriene is not aromatic.
Removing one hydrogen from the intervening CH2 group...
Removing one hydrogen from the intervening CH2 group...
2.8K
Five-Membered Heterocyclic Aromatic Compounds: Overview
3.8K
Heterocyclic aromatic compounds are cyclic compounds that are aromatic and have one or more heteroatoms—atoms other than carbon, in the ring. Depending upon the number of atoms present in the ring, they can be either five or six-membered. Examples of five-membered heterocyclic aromatic compounds include pyrrole, furan, thiophene, and imidazole. Pyrrole consists of one nitrogen atom having one lone pair of electrons. Furan and thiophene have one oxygen and one sulfur heteroatom,...
3.8K
Diels–Alder Reaction Forming Cyclic Products: Stereochemistry
3.8K
The Diels–Alder reaction is one of the robust methods for synthesizing unsaturated six-membered rings. The reaction involves a concerted cyclic movement of six π electrons: four π electrons from the diene and two π electrons from the dienophile.
3.8K
Adrenergic Agonists: Chemistry and Structure-Activity Relationship
2.6K
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
2.6K
[3,3] Sigmatropic Rearrangement of 1,5-Dienes: Cope Rearrangement
2.6K
The Cope rearrangement is classified as a [3,3] sigmatropic shift in 1,5-dienes, leading to a more stable, isomeric 1,5-diene. The reaction involves a concerted movement of six electrons, four from two π bonds and two from a σ bond, via an energetically favorable chair-like transition state.
2.6K

