Product name: N-Desmethyl Galanthamine
Synonym name: Norgalantamine; Norgalanthamine；N-Desmethylgalantamine
Catalogue No.: BP4434
Cas No.: 41303-74-6
Formula: C₁₆H₁₉NO₃
Mol Weight: 273.332
Botanical Source:
Type of Compound:

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle

Storage: Store in a well closed container, protected from air and light. Put into refrigerate or freeze for long term storage.
Whenever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20℃. Generally, these will be useable for up to two weeks.

The product could be supplied from milligrams to grams
Inquire for bulk scale.

For Reference Standard and R&D, Not for Human Use Directly.

HPLC of N-Desmethyl Galanthamine

HNMR of N-Desmethyl Galanthamine

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Alzheimer's Disease (AD), as a progressive neurodegenerative disease, presents a serious challenge to global public health due to its complex pathological mechanisms, including β - amyloid (A β) deposition, excessive phosphorylation of Tau protein, cholinergic neurotransmission defects, neuroinflammation, and oxidative stress. Among various treatment strategies, acetylcholinesterase inhibitors (AChEIs) based on the cholinergic hypothesis are currently the first-line drugs for symptomatic treatment of AD. Galanthamine, an isoquinoline alkaloid derived from plants in the Alliaceae family, has become one of the widely used standard therapeutic drugs in clinical practice due to its unique dual mechanism of reversible inhibition of acetylcholinesterase (AChE) and conformational regulation of neuronal nicotinic acetylcholine receptors (nAChRs).

During the in vivo metabolism of drugs, their metabolites are often not only eliminated end products, but may also have independent biological activity, and may even contribute to or affect the overall efficacy and safety of the parent drug. N-Desmethyl Galanthamine (also known as N-Norgalanthamine, CAS number: 41303-74-6) is one of the main active metabolites of Galanthamine in the human body. Early studies have confirmed that N-demethylgalantamine itself exhibits inhibitory activity against electric eel acetylcholinesterase (EeAChE) (IC50=2.76 μ M), suggesting its potential direct contribution in AD treatment. With the deepening understanding of the pathological network of AD, research has found that the effect of N-demethylated galantamine may go beyond simple cholinesterase inhibition, involving potential regulation of multiple molecular targets closely related to AD pathological processes such as AMPK, Bcl-2 family, Notch, etc.

This article aims to provide a systematic review of N-demethylagalantamine, an important natural metabolite, and explore its chemical nature, sources, pharmacological activity, multi-target mechanism of action, and pharmacological characteristics. It also looks forward to its clinical application prospects as a novel lead compound or adjuvant therapy strategy for Alzheimer's disease.

Chemical structure and physicochemical properties

N-demethylated galantamine is a metabolite formed by the N-demethylation reaction of galantamine catalyzed by the cytochrome P450 enzyme system (mainly CYP2D6 and CYP3A4) in the liver. Its chemical name is (4aS, 6R, 8aS) -3-hydroxy-1,2,4a, 5,6,7,8,8a-octahydro-6-methylpyrrolo [3,2,1-de] phenanthrene-9-ol. The most significant difference in its molecular structure compared to the parent compound galantamine is that the methyl group on the tertiary amine nitrogen atom (N-methyl) is removed and converted to a secondary amine structure.

This structural change directly affects its physicochemical properties. Its molecular weight is 273.3320, slightly lower than galantamine (287.35). The calculated lipid water partition coefficient (LogP) is 1.5044, indicating moderate lipophilicity. However, compared to galantamine (LogP of about 1.8), its lipophilicity slightly decreases due to a slight increase in polarity after demethylation. The topological polar surface area (TPSA) is 50.72 Å ², reflecting the hydrogen bonding ability provided by two hydroxyl groups and one secondary amine nitrogen atom in the molecule. The predicted water solubility value is 6.0636 mg/L, which belongs to the category of slight solubility. However, under physiological pH conditions, it forms salts due to protonation of nitrogen atoms, and its actual solubility may increase, which is beneficial for its distribution in the body.

It is particularly crucial that, based on its structural characteristics and computational model predictions, N-demethylated galantamine has a high blood-brain barrier (BBB) permeability. This is a prerequisite for it to exert pharmacological effects in the central nervous system for AD research. In addition, preliminary pharmacological risk assessment showed a negative hERG inhibition risk and an Ames test result of 0.0 (negative), indicating a low potential risk of arrhythmia and genetic toxicity, providing a favorable safety starting point for its further development.

Plant sources and extraction methods

N-demethylated galantamine, as an in vivo metabolite of galantamine, has received limited reports of direct plant sources. However, its parent compound galantamine is widely present in various Amaryllidaceae plants, such as:
1. Snow slice lotus genus Like summer snow sliced lotus（Leucojum aestivum）It is the main plant source for commercial extraction of galantamine.
2. Allium genus Like yellow flowered garlic（Lycoris aurea）Red flowered garlic（Lycoris radiata）。
3. Narcissus genus Like daffodils（Narcissus pseudonarcissus）。
4. Garland genus For example, Waldemarn（Galanthus woronowii）Wait.

In plants, N-demethylated galantamine may exist in the form of trace alkaloids, but more importantly, it is obtained through post extraction modification or total synthesis of galantamine.
* Extraction and Separation If directly searching from plant materials containing galantamine, the process is similar to galantamine extraction: after drying the plant materials and crushing them, extract them with alcohols (such as methanol, ethanol) or dilute acid solutions, concentrate them, alkalize them, and then extract the total alkaloids with organic solvents (such as chloroform, ethyl acetate). Subsequently, fine separation was performed using techniques such as silica gel column chromatography, high-performance liquid chromatography (HPLC), or counter current chromatography, and the structure was identified by mass spectrometry (MS) and nuclear magnetic resonance (NMR). However, due to its extremely low content in plants, this pathway is inefficient.
* Biotransformation and Chemical Synthesis A more practical method is biotransformation(Using microorganisms or enzyme systems for specific N-demethylation of galantamine) and chemical synthesis Chemical synthesis usually starts with inexpensive and readily available raw materials such as piperonal, and constructs its four ring skeleton through multiple reactions, selectively introducing hydroxyl and secondary amine functional groups. The fully synthetic route can achieve gram level or even larger scale preparation, which is the main means to meet the needs of pharmacological research.

Pharmacological activity research

The core pharmacological activity of N-demethylgalantamine stems from its ability to inhibit acetylcholinesterase. The experiment confirmed that its half maximal inhibitory concentration (IC50) for acetylcholinesterase (EeAChE) in electric eels was 2.76 μ M. Although its inhibitory efficacy is weaker than that of galantamine (IC50 of approximately 0.35 μ M), its activity is still significant, indicating that after taking galantamine, the N-demethylated galantamine produced in the body can continue to contribute to the inhibition of AChE, prolonging and possibly enhancing the cholinergic potentiation response of the parent drug.

In addition to its classical acetylcholinesterase inhibitory activity, an increasing number of studies suggest that N-demethylgalantamine may have broader neuroprotective and disease modifying potential, which is consistent with the multi-target pathological mechanism of AD
1. Neuroprotective effect In cell models, N-demethylagalantamine may alleviate neuronal apoptosis induced by A β oligomers, glutamate excitotoxicity, or oxidative stress by upregulating the expression of anti apoptotic proteins Bcl-2 and Mcl-1, while inhibiting pro apoptotic signals.
2. The impact on A β pathology As an AChE inhibitor, it may indirectly affect A β metabolism, as AChE itself can promote A β aggregation into plaques. In addition, some studies speculate that it may affect the generation of A β by regulating the activity or expression of APP processing enzymes (such as BACE1).
3. Anti inflammatory and immune regulation By potentially regulating inflammatory signaling pathways such as TLR4/NF - κ B, N-demethylated galantamine may inhibit excessive activation of microglia and astrocytes, reducing neuroinflammation. Its potential impact on IDO1 also suggests that it may be involved in tryptophan metabolism and immune regulation.
4. Metabolism and clearance regulation The potential effects on targets such as AMPK and ABCA1 suggest that they may affect cellular energy homeostasis and cholesterol reverse transport, which is closely related to the clearance of A β.

Mechanism of action and molecular targets

The mechanism of action of N-demethylagalantamine exhibits multi-target characteristics, not limited to cholinesterase inhibition, and may form a synergistic network:

1. Core target: Acetylcholinesterase (AChE)

   • effect Reversible binding to the catalytic active site of AChE prevents the hydrolysis of acetylcholine (ACh), increases the level of ACh in synaptic cleft, and directly improves cholinergic neurotransmission defects.

2. Targets related to neuroprotection and apoptosis regulation

   • Bcl-2 family (Bcl-2, Mcl-1)Upregulation of the expression of these anti apoptotic proteins stabilizes mitochondrial outer membrane permeability, prevents cytochrome C release, and thus inhibits the intrinsic apoptotic pathway of neurons.
   • AMPK（PRKAA1）AMPK is a cellular energy sensor. Its activation may enhance neuronal resistance to metabolic stress by promoting autophagy, improving mitochondrial function, inhibiting the mTOR pathway, and possibly promoting A β clearance.
   • Notch1 The Notch signaling pathway plays a crucial role in neural development, synaptic plasticity, and cell fate determination. In AD, Notch signal dysregulation may be associated with cognitive impairment. Regulating Notch1 may help maintain neuronal function and survival.

3. A β metabolism and clearance related targets

   • BACE1β - secretase is a key rate limiting enzyme for the generation of A β. Potential downregulation of BACE1 activity or expression can directly reduce the production of A β.
   • ABCA1 Cholesterol transporter, which mediates the efflux of cholesterol and phospholipids from the cell to apolipoprotein A-I, is a key step in the formation of high-density lipoprotein. In the brain, ABCA1 promotes the lipidation of A β and accelerates its clearance through the blood-brain barrier. Upregulation of ABCA1 expression is a potential disease modification strategy.
   • APP Possible impact on APP processing through non starch derived pathways.

4. Neuroinflammation and immune related targets

   • TLR4 Pattern recognition receptors recognize damage related molecular patterns such as A β, triggering NF - κ B-mediated inflammatory responses. Inhibiting TLR4 signaling can alleviate neuroinflammation.
   • IDO1 Indoleamine 2,3-dioxygenase 1 catalyzes the metabolism of tryptophan along the kynurenine pathway. In AD, IDO1 activation leads to the accumulation of neurotoxic metabolites and depletion of tryptophan, participating in immune suppression and neurotoxicity. Inhibition of IDO1 may have neuroprotective effects.

5. Nuclear receptor target

   • RARA Retinoic acid receptor alpha. Retinoic acid signaling plays an important role in memory formation, synaptic plasticity, and A β clearance. As a potential RARA modulator, N-demethylgalantamine may exert neuroprotective effects through this pathway.

This multi-target spectrum of action makes it possible to simultaneously intervene in multiple core pathological processes of AD, extending from symptom improvement (cholinergic enhancement) to disease modification (neuroprotection, reduction of A β, anti-inflammatory).

Evaluation of drug properties and pharmacokinetics

Based on calculations and limited experimental data, N-demethylgalantamine has shown certain potential as a drug.

• Absorption, distribution, metabolism, excretion (ADME) prediction：

  • absorb Moderate LogP and TPSA indicate that it may have good oral bioavailability and can be absorbed by the intestine through passive diffusion.
  • distribution The high blood-brain barrier permeability prediction is its greatest advantage as a central nervous system drug, ensuring its effective distribution to brain tissue targets. Small molecular weight and moderate lipophilicity are the basis of its BBB penetration ability.
  • Metabolism As a metabolite of galantamine, it may undergo further glucuronidation or sulfation binding reactions, generating more polar metabolites that are excreted by the kidneys. Its secondary amine structure may cause its metabolic pathway to differ from that of the parent organism, and further in vitro liver microsomal experiments are needed for verification.
  • excretion Expected to be primarily excreted through the kidneys in the form of prototypes or conjugates.

• Preliminary Safety Assessment：

  • HERG inhibition negative Reduced the risk of QT interval prolongation and apical torsion type ventricular tachycardia, which are important reasons for many drug development failures.
  • Ames test negative Preliminary indications suggest no direct genetic toxicity and good safety.
  • Still needed evaluation Comprehensive preclinical toxicology studies are required, including subacute/chronic toxicity testing, reproductive toxicity, safety pharmacology (detailed effects on cardiovascular, respiratory, and central nervous systems), etc.

• PK/PD relationship with galantamine In the clinical treatment of galantamine, N-demethylated galantamine is the main active metabolite, and its blood concentration is correlated with the parent drug. Its presence may help smooth the drug time curve of galantamine, prolong the duration of action, and have an impact on overall efficacy and safety (especially cholinergic side effects). The genetic polymorphism of CYP2D6 metabolic enzymes among individuals can affect the conversion rate of galantamine to N-demethylated galantamine, which may be one of the factors leading to individual differences in the efficacy and adverse reactions of galantamine.

Clinical application prospects and prospects

The clinical application prospects of N-demethylgalantamine can be viewed from the following dimensions:

1. As a collaborative contributor to the efficacy of galantamine and a starting point for PK optimization Clarifying the exposure effect relationship of N-demethylated galantamine in existing treatment regimens can help to more accurately understand the overall efficacy of galantamine. By adjusting the dosing regimen or developing sustained-release formulations, optimizing the ratio of parent drug to metabolites, more stable and long-lasting clinical effects may be achieved, while reducing side effects caused by fluctuations in blood drug concentration.

2. As a leading compound for novel multi-target AD therapy Its unique multi-target mechanism of action (cholinesterase inhibition, neuroprotection, potential anti A β, anti-inflammatory) gives it the potential to be developed as a new generation of disease modifying therapies. Through structural optimization For example, introducing specific functional groups onto its skeleton can:

   • Enhance the inhibitory efficacy against AChE or other key targets such as BACE1 and IDO1.
   • Further optimize pharmacokinetic properties (such as improving oral bioavailability and prolonging half-life).
   • Improve target selectivity and reduce off target risk.
   • development Prodrug strategy Design N-demethylagalantamine as a prodrug and release it in specific parts of the body (such as the brain) to enhance targeting.

3. Components of Combination Therapy Strategy Given the complexity of AD, combination therapy is the future trend. N-demethylated galantamine or its derivatives can be used in combination with drugs targeting different pathways (such as A β immunotherapy, Tau protein inhibitors, anti-inflammatory drugs) to produce synergistic effects and more comprehensively curb disease progression.

4. Potential applications beyond AD Its neuroprotective, anti apoptotic, and anti-inflammatory properties also suggest that it may have research value in other neurodegenerative diseases (such as Parkinson's disease, amyotrophic lateral sclerosis), cerebrovascular diseases (such as ischemic stroke), or neuropathic pain.

However, pushing it into clinical practice also faces challenges: requiring significant funding and time investment for systematic preclinical development and clinical trials; It is necessary to clarify the dominant mechanism and potential unexpected effects in its multi-target action; Need to address the cost issue of its synthesis or large-scale production.

Conclusion

N-demethylated galantamine, initially viewed as a metabolic end product of galantamine, is gradually demonstrating its significant value as a natural product molecule with independent pharmacological activity and multi-target intervention potential. It not only explains the source of some clinical effects of galantamine, but more importantly, its neuroprotective, anti apoptotic, and potential disease modifying activities beyond acetylcholinesterase inhibition provide new ideas and lead structures for drug development in Alzheimer's disease.

The in-depth study of N-demethylgalantamine, from chemical structure to pharmacological mechanism, from drug prediction to application prospects, reflects the shift of modern natural product pharmacology from the paradigm of "single component single target" to "multi-component multi-target network regulation". In the future, through in-depth elucidation of molecular mechanisms, rational structural modifications, and rigorous preclinical and clinical evaluations, N-demethylgalantamine is expected to move from behind the scenes to the forefront. It not only serves as an important puzzle for understanding the effects of existing drugs, but also has the potential to generate a new generation of innovative therapeutic drugs for combating neurodegenerative diseases, bringing new hope to billions of AD patients.