Synonym name: 1,2-Dimethoxynoraporphine; N-Nornuciferine; N-Desmethylnuciferine; Sanjoinine Ia; Daechualkaloid E
Catalogue No.: BP1000
Cas No.: 4846-19-9
Formula: C₁₈H₁₉NO₂
Mol Weight: 281.355
Botanical Source: Alkaloid from Nelumbo lutea (Nelumbonaceae) and Colubrina faralaotra (Rhamnaceae), also from the Annonaceae, Magnoliaceae, Menispermaceae and Monimiaceae

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
Can be supplied from milligrams to grams.

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

HPLC of N-nornuciferine

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

Introduction/Overview

Natural products, as an important source of drug discovery, hold an irreplaceable position in modern pharmacological research. Lotus leaf (Nelumbo nucifera Gaertn), as a traditional Chinese medicinal herb, has been widely studied for its many bioactive components. N-Nornuciferine (CAS No.: 4846-19-9) is an important apophine alkaloid found in lotus leaf, and has attracted attention in recent years due to its remarkable pharmacological activity and potential clinical value. This compound not only demonstrates regulatory ability over multiple cardiovascular-related targets but also demonstrates strong inhibitory effects on the drug-metabolizing enzyme CYP2D6, suggesting its potential role in drug interactions and cardiovascular disease treatment.

This paper aims to systematically review the chemical structure, physicochemical properties, plant origin, and extraction methods of N-desmethyl Lotus Leaf, delve into its pharmacological activity and mechanism of action, evaluate its druggability and pharmacokinetic characteristics, and finally look ahead to its clinical application prospects, providing theoretical basis and reference for subsequent basic and applied research.

Chemical structure and physicochemical properties

N-Normethaline belongs to the apophyll alkaloids, with the molecular formula C19H23NO2 and a molecular weight of 281.3550. Its structural feature is a typical alkaloid backbone, containing a demethylated nitrogen atom that imparts its unique chemical activity. In terms of physicochemical properties, the LogP value of N-desmethylene is 3.2819, indicating moderate lipid solubility, which is beneficial for cell membrane penetration and distribution in vivo. Its topological polar surface area (TPSA) is 30.4900, and its lower polarity helps cross the blood-brain barrier (BBB), which matches its high blood-brain barrier permeability. Additionally, the compound has a low water solubility (0.2494), suggesting it may exist in the body as liposomals or binding proteins.

It is worth noting that N-Normethaline has hERG channel inhibitory activity, suggesting potential risks to cardiac electrophysiological safety and requiring special attention during drug development. Additionally, the Ames test result was 0.6, indicating a low genotoxicity risk and a solid safety foundation.

Plant Origins and Extraction Methods

N-Normethrinic Leaf Alkaloid is mainly found in the leaves of Nelumbo nucifera Gaertn and is an important component of apophine alkaloids in Lotus Leaf. As a traditional Chinese medicinal herb, lotus leaves are widely distributed across many regions of Asia, especially China, Japan, and India. It has a long history of medicinal use, mainly used to treat obesity, hyperlipidemia, and cardiovascular diseases.

Common methods for extracting N-demethylated leaf alkali include organic solvent extraction, acid-base adjustment, liquid-liquid partitioning, and column chromatography purification. Generally, ethanol or methanol is used as extraction solvents, and extraction efficiency is improved through ultrasound-assisted extraction or reflux extraction. Subsequently, alkaloids were separated from plant substrates using acid-base adjustment methods, and purification was achieved using silica gel column chromatography and reversed-phase high-performance liquid chromatography (RP-HPLC). In recent years, supercritical fluid extraction and molecular blotting technologies have also been explored to improve extraction purity and efficiency.

Optimizing the extraction process not only affects the yield of N-desmethaline but also relates to maintaining its biological activity and removing impurities, making it a key link for achieving large-scale production and clinical application.

Pharmacological activity research

Pharmacological activity studies of N-desmethylene focus on its protective effects on the cardiovascular system and its regulatory ability to metabolize drug metabolism enzymes. Multiple in vitro and in vivo experiments have shown that this compound can significantly inhibit the activity of the cytochrome P450 enzyme CYP2D6, with an IC50 of 3.76 μM and a Ki value of 2.34 μM, demonstrating a strong enzymatic inhibitory effect. This characteristic suggests that N-Normethaline may affect the metabolism of various CYP2D6 substrate drugs, posing potential drug interaction risks.

In cardiovascular protection, N-desmethylene acts by regulating multiple key targets, including selectin (SELP), peroxisome proliferator-activated receptor γ (PPARG), angiotensin-converting enzyme (ACE), protein kinase B (AKT1), β2 adrenergic receptor (ADRB2), potassium channel protein KCNH2, nitric oxide synthase type 3 (NOS3), intercellular adhesion molecule (ICAM1), vascular cell adhesion molecule (VCAM1) and sodium-calcium exchange protein (SLC8A1), among others. The regulation of these targets involves vasodilation, inflammatory responses, myocardial protection, and hemodynamic modulation.

Animal model studies have shown that N-Normethyrosine can lower blood pressure, improve myocardial ischemia-reperfusion injury, inhibit inflammatory responses in vascular endothelial cells, alleviate atherosclerotic lesions, and possess significant cardiovascular protective potential. Moreover, its antioxidant and anti-inflammatory effects provide important mechanistic support for its cardiovascular protective effects.

Mechanism of action and molecular targets

The mechanism of action of N-Normethaline is complex and diverse, mainly achieving its pharmacological effects through coordinated regulation of multiple targets and pathways. Its inhibitory effect on CYP2D6 may be achieved through competitive binding with enzyme active sites, affecting the drug's metabolic kinetics and suggesting potential risks in combination therapy.

In terms of cardiovascular protection, N-desmethylene regulates cell adhesion molecules such as SELP, ICAM1, and VCAM1, weakening the adhesion and migration of inflammatory cells and inhibiting vascular inflammatory responses. By activating the PPARG and AKT1 signaling pathways, endothelial cell survival and functional recovery are promoted, enhancing vasodilatory capacity. The inhibitory effect of ACEs helps lower angiotensin II levels, alleviating vasoconstriction and hypertension.

Activation of ADRB2 regulates myocardial contractility and heart rate, regulation of the KCNH2 channel influences cardiac repolarization, NOS3 promotes nitric oxide production, improving vascular endothelial function. SLC8A1 regulates calcium homeostasis within myocardial cells, protecting them from calcium overload damage. The combined regulation of these targets enables N-desmethylene to play a protective role in multiple pathological stages of cardiovascular diseases.

Molecular docking and cell signaling pathway analysis further confirmed the high affinity and regulatory ability of N-desmethylene with the above targets, providing a molecular basis for its pharmacological effects.

Druggability evaluation and pharmacokinetics

From the perspective of druggability, N-Normethine has certain advantages and challenges. Its moderate molecular weight (281.3550) and LogP value (3.2819) comply with the Lipinski rule, facilitating oral absorption and internal distribution. A lower TPSA (30.4900) and high blood-brain barrier permeability suggest it may act in the central nervous system, expanding its potential indications.

However, its low water solubility (0.2494) may limit its bioavailability, and solubility needs to be improved through formulation technology. HERG channel inhibition suggests potential cardiotoxicity risks and requires early safety evaluation and structural optimization during drug development. Ames trial results show that its genotoxicity risk is low, providing some assurance for clinical development.

Pharmacokinetic research is still in its early stages, and metabolic pathways and clearance mechanisms in vivo have not been fully elucidated. Given its strong inhibitory effect on CYP2D6, N-desmethyl phylline may affect its own and other drug metabolisms, so special attention should be paid to drug interactions and dose adjustments.

Future research should focus on systematic evaluation of in vivo pharmacokinetics, toxicology, and pharmacodynamics, integrating drug design to optimize safety and efficacy.

Prospects and outlooks for clinical applications

N-Normethine Leaf Alkaloid, as a natural apophine alkaloid, demonstrates broad clinical application potential due to its multi-target cardiovascular protective effects and significant inhibition of CYP2D6. Its therapeutic value in hypertension, atherosclerosis, myocardial ischemia, and inflammation-related cardiovascular diseases deserves further exploration.

Additionally, due to its high blood-brain barrier permeability, N-nomethaline may be used in the treatment of neurocardiovascular diseases, such as cerebrovascular disease and neurogenic heart disease, expanding its indications.

However, clinical translation still faces many challenges, including improving water solubility and bioavailability, controlling cardiotoxicity risks, and evaluating drug interactions. In the future, these limitations will need to be overcome through structural modification, dosage form optimization, and combination therapy strategies.

The launch of multicenter clinical trials will be a key step in verifying its safety and efficacy. At the same time, by integrating modern drug design and systems biology techniques, in-depth analysis of its network of action and molecular mechanisms will promote the advancement of N-Normethaline toward clinical application.

Conclusion

N-Normethrin, an important apophine alkaloid in lotus leaves, has attracted widespread attention due to its unique chemical structure and significant pharmacological activity, especially in cardiovascular protection and drug metabolism enzyme inhibition. Its multi-target regulatory mechanism provides new ideas and strategies for comprehensive treatment of cardiovascular diseases.

Despite challenges such as insufficient water solubility and potential cardiotoxicity, N-Normethaline still has a solid druggability foundation and development potential. In the future, through systematic pharmacokinetics, safety evaluation, and clinical research, it is expected to transform from natural products to clinical drugs, benefiting a wide range of patients.

In summary, N-Normethaline not only enriches the research content of natural product pharmacology, but also provides valuable molecular templates and theoretical support for the development of innovative cardiovascular drugs. We look forward to more in-depth basic and applied research in the future to advance its clinical applications.