科鲁西坦
描述
库鲁拉西坦，也称为其化学名称 N-(2,3-二甲基-5,6,7,8-四氢呋喃[2,3-b]喹啉-4-基)-2-(2-氧代-1-吡咯烷基)乙酰胺，是属于乙酰胺类家族的促智化合物。 它最初由三菱田边制药株式会社开发，用于治疗阿尔茨海默病，但现在已被广泛研究，以探索其在增强认知功能、记忆力和情绪方面的潜在益处 .
科学研究应用
Cognitive Disorders
Coluracetam has been explored in various clinical settings for its effects on cognitive disorders:
- Alzheimer’s Disease: Initial studies focused on its potential to improve cognitive function in Alzheimer’s patients. While promising results were observed in animal models regarding memory restoration, human trials yielded inconclusive results .
- Depression and Anxiety: Coluracetam was investigated in phase II clinical trials for major depressive disorder and anxiety. Although these studies were ultimately discontinued due to failure to meet endpoints, preliminary findings suggested potential anxiolytic effects without impacting serotonin levels .
Case Studies
Several case studies have documented the effects of Coluracetam on cognitive enhancement:
- Visual Perception and Reasoning: A study assessed the impact of Coluracetam on visual perception and abstract reasoning. Participants demonstrated improvements in analytical thinking and spatial orientation after administration .
- Memory Improvement in Impaired Subjects: Research involving rats with chemically induced memory deficits showed significant enhancements in working memory following Coluracetam treatment over an eight-day period .
Summary of Research Findings
The following table summarizes key findings from various studies on Coluracetam:
| Study Focus | Key Findings | Population Studied |
|---|---|---|
| Alzheimer’s Disease | Increased acetylcholine levels; inconclusive human trial results | Animal models; human trials |
| Major Depression & Anxiety | Potential anxiolytic effects; discontinued phase II trials | Human subjects |
| Cognitive Enhancement | Improved visual perception, reasoning, and analytical thinking | Case study participants |
| Memory Restoration | Significant improvement in working memory in impaired rats | Animal models |
作用机制
库鲁拉西坦主要增强高亲和力胆碱摄取 (HACU)，它是乙酰胆碱合成的限速步骤，乙酰胆碱是学习和记忆的重要神经递质 . 通过增加胆碱的可用性，库鲁拉西坦可促进乙酰胆碱的产生，从而增强认知功能。 它还调节胆碱转运蛋白调节系统，导致持久的促认知作用 .
类似化合物：
吡拉西坦： 第一个乙酰胺类促智药，以其增强认知的作用而闻名。
安奈西坦： 另一种具有抗焦虑和认知益处的乙酰胺类药物。
奥拉西坦： 以其兴奋作用和认知增强作用而闻名。
库鲁拉西坦的独特性： 库鲁拉西坦的独特性在于其增强高亲和力胆碱摄取的特定机制，这在其他乙酰胺类药物中未见。 这种独特的机制使其在改善胆碱能功能受损的疾病中的记忆力和学习方面特别有效 .
生化分析
Biochemical Properties
The primary mechanism of action for coluracetam is its ability to increase the uptake of choline into neurons . Choline is a precursor to the neurotransmitter acetylcholine, which plays a crucial role in cognitive processes such as memory formation, learning, and attention . Coluracetam achieves this by interacting with the high-affinity choline transporter (HACU), which is responsible for transporting choline across the cell membrane and into neurons . By enhancing the efficiency of the choline transport system, coluracetam promotes the synthesis and release of acetylcholine .
Cellular Effects
Coluracetam works mainly by increasing the levels of acetylcholine, a crucial neurotransmitter, and modulating choline uptake in the brain . Its unique mechanisms make it interesting for cognitive enhancement and potential therapeutic uses . Enhancement of Acetylcholine Synthesis: Coluracetam boosts acetylcholine synthesis . Acetylcholine is vital for learning and memory . The brain uses choline to produce acetylcholine . By enhancing this process, coluracetam improves cognitive functions .
Molecular Mechanism
Coluracetam enhances high-affinity choline uptake (HACU), which is the rate-limiting step of acetylcholine (ACh) synthesis . Studies have shown coluracetam to improve learning impairment on a single oral dose given to rats which have been exposed to cholinergic neurotoxins . Subsequent studies have shown that it may induce long-lasting procognitive effects in cholinergic neurotoxin-treated rats by changing the choline transporter regulation system .
Dosage Effects in Animal Models
Most of the research on coluracetam was done on animals rather than humans, so there are no universally accepted dosing guidelines . In a 2010 animal study, coluracetam improved artificially-induced memory deficits without producing any significant side effects .
Transport and Distribution
Coluracetam is fat-soluble, so it needs fats for optimal absorption . It’s usually taken sublingually (under the tongue) or orally . This method enhances its bioavailability .
Subcellular Localization
Given its mechanism of action, it is likely that coluracetam interacts with neurons in the brain where it enhances the uptake of choline, a precursor to the neurotransmitter acetylcholine .
Side effects and long-term safety remain areas requiring more comprehensive research .
准备方法
合成路线和反应条件： 库鲁拉西坦是通过一个多步骤过程合成的，该过程涉及 2,3-二甲基-5,6,7,8-四氢呋喃[2,3-b]喹啉与 2-氧代-1-吡咯烷基乙酰胺的反应。关键步骤包括：
喹啉核心的形成： 这涉及在受控条件下进行环化反应。
吡咯烷基的连接： 此步骤通常需要使用偶联试剂和催化剂来确保高产率和纯度。
工业生产方法： 库鲁拉西坦的工业生产遵循类似的合成路线，但规模更大。该过程针对效率、成本效益和遵守监管标准进行了优化。关键考虑因素包括：
反应可扩展性： 确保反应能够在不降低产率或纯度的情况下进行放大。
纯化： 采用结晶和色谱等技术，以达到所需的纯度水平。
化学反应分析
反应类型： 库鲁拉西坦会经历各种化学反应，包括：
氧化： 这可以在特定条件下发生，导致形成氧化衍生物。
还原： 还原反应可以改变官能团，可能改变化合物的活性。
取代： 取代反应可以引入不同的官能团，这些官能团可能增强或降低其促智特性。
常用试剂和条件：
氧化剂： 例如高锰酸钾或过氧化氢。
还原剂： 包括硼氢化钠或氢化铝锂。
催化剂： 通常用于取代反应中，以提高反应速度和产率。
主要产物： 这些反应的主要产物是库鲁拉西坦的修饰形式，它们可能具有不同的药理学特性。这些衍生物通常用于研究结构-活性关系。
相似化合物的比较
Piracetam: The first racetam nootropic, known for its cognitive-enhancing effects.
Aniracetam: Another racetam with anxiolytic and cognitive benefits.
Oxiracetam: Known for its stimulating effects and cognitive enhancement.
Uniqueness of Coluracetam: Coluracetam is unique due to its specific mechanism of enhancing high-affinity choline uptake, which is not observed in other racetams. This distinct action makes it particularly effective in improving memory and learning in conditions where cholinergic function is compromised .
生物活性
Coluracetam is a synthetic compound originally developed in Japan, primarily recognized for its role as a cognitive enhancer. It belongs to a class of drugs known as racetams and has garnered attention for its potential neuroprotective properties and effects on memory and learning. The compound acts primarily as a high-affinity choline uptake (HACU) enhancer, which is crucial for the synthesis of acetylcholine (ACh), a neurotransmitter associated with memory and cognitive function.
Coluracetam's primary mechanism involves enhancing the uptake of choline in the brain, which is vital for ACh production. This is achieved through its interaction with the choline transporter (CHT1), leading to increased availability of choline for ACh synthesis. Research indicates that Coluracetam may also modulate the efficiency of HACU, thereby enhancing synaptic ACh levels without directly affecting acetylcholinesterase (AChE) activity, which breaks down ACh in the synapse .
Key Mechanisms:
- High-Affinity Choline Uptake (HACU): Coluracetam enhances HACU activity, facilitating greater choline availability for ACh synthesis .
- Neuroprotective Effects: It has been shown to reverse deficits in ACh levels in animal models, particularly in cases where ACh depletion occurs due to neurotoxic agents .
- Cognitive Enhancement: The compound has demonstrated improvements in various cognitive functions, including memory and learning, particularly in models with induced cognitive deficits .
Observational Studies
Coluracetam has been tested in various animal models to assess its effects on cognitive function. In studies involving rats treated with AF64A (a neurotoxin that induces cholinergic deficits), Coluracetam significantly reversed the decline in ACh levels and improved cognitive performance metrics such as spatial learning and memory retention .
Case Studies
A notable case study examined the effects of Coluracetam on a 36-year-old male participant over three months. The participant reported improvements in visual perception, abstract reasoning, pattern recognition, and analytical thinking, although there was a slight decline in spatial orientation scores. Statistical analysis revealed no significant differences between pre- and post-test scores across most cognitive domains, suggesting that while subjective improvements were noted, they may not have been statistically robust .
Summary of Cognitive Effects from Case Study:
| Cognitive Domain | Pretest Score | Posttest Score | Change | Significance |
|---|---|---|---|---|
| Visual Perception | X | Y | +Δ | NS |
| Abstract Reasoning | X | Y | +Δ | NS |
| Pattern Recognition | X | Y | +Δ | NS |
| Spatial Orientation | X | Y - 5 | -5 | NS |
| Analytical Thinking | X | Y | +Δ | NS |
NS = Not Significant
Pharmacological Studies
Pharmacological studies have demonstrated that Coluracetam enhances cognitive function through its action on the HACU system. In repeated administration studies, it was found that Coluracetam could induce long-lasting pro-cognitive effects by modifying choline transporter regulation systems .
Neurochemical Effects
In rodent studies, administration of Coluracetam resulted in:
属性
IUPAC Name |
N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)-2-(2-oxopyrrolidin-1-yl)acetamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C19H23N3O3/c1-11-12(2)25-19-17(11)18(13-6-3-4-7-14(13)20-19)21-15(23)10-22-9-5-8-16(22)24/h3-10H2,1-2H3,(H,20,21,23) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
PSPGQHXMUKWNDI-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=C(OC2=NC3=C(CCCC3)C(=C12)NC(=O)CN4CCCC4=O)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C19H23N3O3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID60159386 |
Source
|
| Record name | Coluracetam | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID60159386 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
341.4 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
135463-81-9 |
Source
|
| Record name | Coluracetam | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=135463-81-9 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Coluracetam [INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0135463819 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Coluracetam | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID60159386 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | COLURACETAM | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/V6FL6O5GR7 | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Retrosynthesis Analysis
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.
Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.
Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
体外研究产品的免责声明和信息
请注意，BenchChem 上展示的所有文章和产品信息仅供信息参考。 BenchChem 上可购买的产品专为体外研究设计，这些研究在生物体外进行。体外研究，源自拉丁语 "in glass"，涉及在受控实验室环境中使用细胞或组织进行的实验。重要的是要注意，这些产品没有被归类为药物或药品，他们没有得到 FDA 的批准，用于预防、治疗或治愈任何医疗状况、疾病或疾病。我们必须强调，将这些产品以任何形式引入人类或动物的身体都是法律严格禁止的。遵守这些指南对确保研究和实验的法律和道德标准的符合性至关重要。
