galanthamine
概要
説明
準備方法
合成経路と反応条件: ガランタミンは、生体模倣酸化カップリング反応、遷移金属触媒反応、転位反応など、様々な方法で合成できます . 主要な合成戦略としては、以下のようなものがあります。
酸化フェノールカップリング: この方法は、フェノールの酸化カップリングを利用したものであり、ガランタミンの全合成において広く研究されています.
遷移金属触媒反応: ヘック反応、エニン環化メタセシス（RCM）、動的キネティック分解などがあります.
工業的製造方法: ガランタミンの工業的製造には、天然源からの抽出または合成による製造が用いられます. 最初の工業プロセスは1959年に開発されました . 近年では、収率向上やコスト削減を目指して、合成経路の最適化が進んでおり、 .
化学反応の分析
反応の種類: ガランタミンは、以下のような様々な化学反応を起こします。
一般的な試薬と条件:
主要な生成物: これらの反応によって生成される主要な生成物には、官能基が修飾された様々なガランタミン誘導体が含まれており、薬理作用が異なる場合があります .
科学的研究の応用
Galanthamine is a naturally occurring compound that has garnered attention for its clinical applications, particularly in the treatment of Alzheimer's disease (AD) . It is derived from plants such as Galanthus nivalis and Narcissus pseudonarcissus .
Scientific Research Applications
Alzheimer's Disease Treatment
- This compound is clinically approved for the treatment of Alzheimer's disease due to its ability to inhibit acetylcholine esterase (AChE) . By blocking the breakdown of acetylcholine in the synaptic cleft, galantamine increases acetylcholine neurotransmission . It also acts as an allosteric modulator of the nicotinic receptor, giving its dual mechanism of action clinical significance .
- Clinical trials have demonstrated that galantamine can significantly improve cognitive function and global function in patients with mild to moderate AD . Studies have shown that galantamine, at recommended doses of 16 mg to 24 mg daily, slows the decline in memory and the ability to perform self-care activities at 6 months and 2 years .
- Long-term treatment with galantamine has been shown to reduce mortality and the decline in cognition and daily living activities in patients with mild to moderate AD .
Cognitive and Neuropathic Conditions
- Early research explored galantamine's use in paralytic and neuropathic conditions, as well as for the reversal of neuromuscular blockade . It has also been studied for its cognitive effects in various psychiatric disorders, including mild cognitive impairment, cognitive impairment in schizophrenia and bipolar disorder, and autism .
- In one study, galantamine reversed scopolamine-induced acute anticholinergic syndrome, which was characterized by drowsiness, disorientation, and delirium .
Dual Cropping for this compound Production
- Innovative approaches have explored the dual cropping of Narcissus pseudonarcissus with grassland-based ruminant production to produce plant-derived this compound . This method involves planting N. pseudonarcissus into existing grassland, which could offer a triple win scenario: (1) maintaining traditional upland farming systems and increasing their economic viability, (2) improving access to AD treatment, and (3) reducing the environmental impacts of this compound production .
- A three-year systems study verified the feasibility of this dual cropping approach, demonstrating that incorporating N. pseudonarcissus into grazed permanent pasture had no detrimental effects on the health or performance of sheep that grazed the pasture .
Data Tables and Case Studies
Efficacy of Galantamine in Alzheimer's Disease
| Metric | Galantamine Group | Placebo Group | P-Value |
|---|---|---|---|
| Change in MMSE scores from baseline | -1.41 | -2.14 | <0.021 |
| Mortality Rate (Hazard Ratio) | 0.58 | N/A | 0.011 |
| Deaths | 33 (3.2%) | 56 (5.5%) | 0.011 |
MMSE = Mini-Mental State Examination
Case Study: Galantamine for Cognition and Global Function
A 6-month, multicenter, double-blind trial was conducted with 636 patients with mild to moderate AD. Patients were randomly assigned to placebo or galantamine and escalated to maintenance doses of 24 or 32 mg/d. The results showed that galantamine significantly improved cognitive function relative to placebo, with treatment effects of 3.9 points (lower dose) and 3.8 points (higher dose) on the ADAS-cog/11 scale at month 6 (p < 0.001 in both cases) . Both doses of galantamine produced a better outcome on CIBIC-plus than placebo (p < 0.05) . At 12 months, mean ADAS-cog/11 and DAD scores had not significantly changed from baseline for patients who received galantamine 24 mg/d throughout the 12 months .
Safety and Tolerability
作用機序
類似化合物との比較
生物活性
Galanthamine is a natural alkaloid derived primarily from the bulbs of plants in the Amaryllidaceae family, particularly from the snowdrop (Galanthus spp.). It has garnered significant attention due to its biological activities, especially its role as an acetylcholinesterase (AChE) inhibitor, making it a crucial compound in the treatment of neurodegenerative diseases such as Alzheimer's disease (AD). This article explores the diverse biological activities of this compound, supported by case studies and research findings.
This compound functions primarily as a reversible inhibitor of AChE, an enzyme responsible for the hydrolysis of acetylcholine (ACh) in the synaptic cleft. By inhibiting AChE, this compound increases the availability of ACh, enhancing cholinergic neurotransmission. This mechanism is particularly beneficial in conditions characterized by cholinergic deficits, such as AD. Additionally, this compound interacts with nicotinic acetylcholine receptors (nAChRs), which may provide neuroprotective effects against β-amyloid toxicity in neurons .
Biological Activities
1. Neuroprotective Effects:
Research indicates that this compound exhibits neuroprotective properties by modulating various neurotransmitter systems. It has been shown to:
- Enhance synaptic plasticity.
- Protect neurons from apoptosis induced by β-amyloid peptides.
- Improve cognitive function in animal models of AD .
2. Antioxidant Properties:
this compound has demonstrated antioxidant activity, which helps mitigate oxidative stress—an important factor in neurodegeneration. Studies have reported that it can reduce lipid peroxidation and increase levels of glutathione, a critical antioxidant in the brain .
3. Anti-inflammatory Effects:
The compound also exhibits anti-inflammatory properties, which may contribute to its therapeutic effects in neurodegenerative diseases. Inflammation is a key component of AD pathology, and this compound's ability to modulate inflammatory responses is beneficial .
Case Study 1: Efficacy in Alzheimer's Disease
A clinical trial assessed the effectiveness of this compound in patients with mild to moderate AD. Results indicated that patients receiving this compound showed significant improvements in cognitive function compared to placebo groups. The study highlighted improvements in both memory and overall cognitive performance, reinforcing its role as a valuable therapeutic agent .
Case Study 2: Synthesis of this compound Derivatives
Recent research focused on synthesizing new derivatives of this compound that incorporate peptide moieties to enhance its pharmacological profile. These derivatives were tested for their AChE inhibitory activity and showed promising results with improved potency and reduced toxicity compared to this compound itself. The study utilized various biochemical assays to evaluate their efficacy .
Data Summary
| Biological Activity | Mechanism | Outcome |
|---|---|---|
| AChE Inhibition | Competitive inhibition at the active site | Increased ACh levels; improved cognition |
| Neuroprotection | Modulation of nAChRs; reduction of β-amyloid toxicity | Enhanced neuronal survival; improved memory |
| Antioxidant Activity | Reduction of oxidative stress markers | Decreased lipid peroxidation; increased GSH levels |
| Anti-inflammatory | Modulation of inflammatory pathways | Reduced neuroinflammation; potential cognitive benefits |
特性
IUPAC Name |
(1S,12S,14R)-9-methoxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6(17),7,9,15-tetraen-14-ol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C17H21NO3/c1-18-8-7-17-6-5-12(19)9-14(17)21-16-13(20-2)4-3-11(10-18)15(16)17/h3-6,12,14,19H,7-10H2,1-2H3/t12-,14-,17-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
ASUTZQLVASHGKV-JDFRZJQESA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN1CCC23C=CC(CC2OC4=C(C=CC(=C34)C1)OC)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CN1CC[C@@]23C=C[C@@H](C[C@@H]2OC4=C(C=CC(=C34)C1)OC)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C17H21NO3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID2045606 |
Source
|
| Record name | Galanthamine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2045606 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
287.35 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Galantamine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014812 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
Crystals from water; decomposition 256-257 °C. Sparingly sol in cold; more sol in hot water. Very sparingly sol in alcohol, acetone. /Hydrochloride/, Fairly soluble in hot water; freely soluble in alcohol, acetone, chloroform. Less sol in benzene, ether., 1.70e+00 g/L |
Source
|
| Record name | GALANTAMINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7361 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Galantamine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014812 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Alzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine-producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The cholinergic system plays a critical role in memory, alongside other important neural functions such as attention, learning, stress response, wakefulness and sleep, and sensory information. Studies show that acetylcholine (ACh) is involved in the modulation of acquisition, encoding, consolidation, reconsolidation, extinction, and retrieval of memory. The gradual loss of cholinergic neurons in Alzheimer’s disease (AD) may, therefore, contribute to the memory loss exhibited by AD patients. Acetylcholinesterase is secreted by cholinergic neurons to rapidly hydrolyze ACh at the synaptic cleft to release acetate and choline. Choline is later recycled back into the presynaptic cholinergic neuron via reuptake by the high-affinity choline transporter. There is some evidence demonstrating the potential involvement of the acetylcholinesterase enzyme in the formation of amyloid fibrils. Galantamine competitively and reversibly inhibits the anticholinesterase enzyme in the CNS (namely in the frontal cortex and hippocampal regions) by binding to the choline-binding site and acyl-binding pocket of the enzyme active site. By blocking the breakdown of ACh, galantamine enhances ACh levels in the synaptic cleft. Nicotinic acetylcholine receptors (nAChR) in the CNS are mostly expressed at the presynaptic neuronal membrane to control the release of multiple neurotransmitters, such as ACh, glutamate, GABA, dopamine, serotonin, norepinephrine. Agonists of nAChRs improve performance in cognitive tasks, while antagonists of nAChR impair cognitive processes. Some studies show a decrease in the expression and activity of nAChRs in patients with AD, which may explain the reduction in central cholinergic neurotransmission in these patients. Galantamine binds to nAChRs at the allosteric site, leading to a conformational change of the receptor, increased ACh release, and increased activity of neighbouring glutaminergic and serotoninergic neurons. The modulation of nAChRs facilitates both excitatory and inhibitory cholinergic transmissions in brain tissues and increases receptor sensitivity. The modulated release of other neurotransmitters by galantamine may also contribute to the upregulation of nAChRs and amelioration of behavioural symptoms in AD., Galantamine, a tertiary alkaloid, is a competitive and reversible inhibitor of acetylcholinesterase. While the precise mechanism of galantamine's action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this mechanism is correct, galantamine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that galantamine alters the course of the underlying dementing process., The cause of cognitive impairment in Alzheimer's Disease is not fully understood, it has been shown that acetylcholine producing neurons degenerate. The cholinergic loss has been correlated with cognitive impairment and a density of amyloid plaques. Galantamine is a tertiary alkaloid and it competes with and is a reversible inhibitor of acetylcholinesterase. The exact mechanism of galantamine is not known, but it is believed to enhance cholinergic function. |
Source
|
| Record name | Galantamine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00674 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | GALANTAMINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7361 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Crystals from benzene | |
CAS No. |
357-70-0, 23173-12-8 |
Source
|
| Record name | (-)-Galantamine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=357-70-0 | |
| 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 | Galantamine [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000357700 | |
| 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 | (+/-)-Galantamine | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0023173128 | |
| 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 | Galantamine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00674 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Galantamine | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=759861 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | Galanthamine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2045606 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | GALANTAMINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/0D3Q044KCA | |
| 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. | |
| Record name | GALANTAMINE, (±)- | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/1T835Z585R | |
| 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. | |
| Record name | GALANTAMINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7361 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Galantamine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014812 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
126-127 °C, 269 - 270 °C (hydrogen bromide salt) |
Source
|
| Record name | GALANTAMINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7361 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Galantamine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014812 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Retrosynthesis Analysis
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| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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