Synonym name: Analeptin; Ethaphene; Oxedrine, BAN; Simpalon; Sympathol
Catalogue No.: BP1352
Cas No.: 94-07-5
Formula: C₉H₁₃NO₂
Mol Weight: 167.208
Botanical Source:

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 Synephrine

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

Introduction/Overview

Obesity has become a global public health challenge, which is closely related to the risk of cardiovascular disease, type 2 diabetes and some cancers. Among numerous weight management strategies, natural products have attracted much attention due to their wide range of sources and potential safety. Synephrine (CAS number: 94-07-5), also known as p-hydroxyforint or Oxedrine, is a phenylethylamine alkaloid extracted from the Rutaceae plant Citrus aurantium (bitter orange). As a sympathomimetic amine, sinomenine is widely used in dietary supplements due to its potential to promote energy expenditure and fat breakdown, claiming to have the effect of assisting weight loss. However, its exact pharmacological effects, molecular mechanisms, and long-term safety still need to be systematically reviewed and scientifically evaluated. This article aims to provide a systematic review of the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, medicinal properties, and clinical application prospects of sinomenine, in order to provide reference for the in-depth research and rational application of this natural product.

Chemical structure and physicochemical properties

The chemical name of Synephrine is 1- (4-hydroxyphenyl) -2-methylaminoethanol, with a molecular formula of C9H13NO2 and a molecular weight of 167.2080. The core of its structure is a phenylethylamine skeleton, with a hydroxyl group attached to the para position of the benzene ring, a β - hydroxyethylamine side chain, and a methyl group attached to the amino group. This structure has similarities with endogenous catecholamines (such as adrenaline, norepinephrine) and ephedrine, but there is only one phenolic hydroxyl group on the benzene ring of sinomenine, which belongs to the monophenolic compound. This affects its affinity and metabolic stability with adrenergic receptors.

From the analysis of physical and chemical properties, the lipid water partition coefficient (LogP) of Simulin is about 0.5075, indicating its moderate lipophilicity. Its topological polar surface area (TPSA) is 52.49 Å ², which conforms to the general characteristics of oral medications. Simulin has good water solubility, with a calculated value of approximately 40.7128 mg/L, which is beneficial for its dissolution and absorption in the gastrointestinal tract. These basic pharmacological parameters suggest that sinomenine has good potential for oral bioavailability. Simulin usually exists in the form of hydrochloride or sulfate to enhance its stability and solubility.

Plant sources and extraction methods

Simulin mainly comes from citrus plants in the Rutaceae family, especially the fruits, peels, and flowers of lime (Citrus aurantium L.). Sour orange, also known as bitter orange or orange peel, has a history of application in traditional medicine. There are significant differences in the content of sinomenine among different varieties, origins, harvesting periods, and plant parts (such as those with higher content in young fruits).

There are various methods for extracting sinomenine, aiming to efficiently and environmentally obtain the target components. Traditional methods include solvent extraction, which commonly involves leaching or reflux extraction using water, methanol, ethanol, or acid aqueous solutions. Modern separation technology has significantly improved purification efficiency and selectivity:
1. Ultrasound assisted extraction/Microwave assisted extraction Utilizing physical fields to enhance mass transfer, shorten extraction time, and improve yield.
2. Column chromatography technology The use of macroporous adsorption resins (such as AB-8, D101), cation exchange resins, or silica gel columns for the separation and purification of crude extracts is a key step in obtaining high-purity sinomenine.
3. High-speed countercurrent chromatography A liquid-liquid distribution chromatography technique that does not require a solid phase carrier and is suitable for preparation grade separation, effectively avoiding irreversible adsorption.
4. Supercritical fluid extraction Using supercritical CO ₂ as the solvent and sometimes adding entrainers (such as methanol), this method has mild conditions and minimal solvent residue, but the equipment cost is relatively high.

The optimization of extraction process usually revolves around parameters such as solvent type, concentration, solid-liquid ratio, temperature, time, and pH value to achieve maximum extraction efficiency and economic feasibility.

Pharmacological activity research

The pharmacological activity research of sinomenine mainly focuses on metabolic regulation, with the core being its sympathetic like effect.

1. Energy metabolism and thermogenesis Simulin, as an alpha - and beta adrenergic receptor agonist, can simulate the activation state of the sympathetic nervous system. Research has shown that it may increase resting energy expenditure by stimulating beta adrenergic receptors (especially beta 3-AR), stimulating lipolysis in white adipose tissue, and activating thermogenesis in brown adipose tissue. Multiple animal experiments and some human trials have shown that supplementing with sinomenine can slightly but significantly increase metabolic rate.
2. Fat metabolism regulation Simulin is believed to promote lipolysis, increase plasma free fatty acid levels, and provide energy substrates for the body. Meanwhile, some studies suggest that it may inhibit the activity of enzymes related to fat synthesis.
3. Appetite suppression Its quasi sympathetic nervous activity may have a slight inhibitory effect on the hypothalamic feeding center, helping to reduce energy intake, but this effect is weaker than classical appetite suppressants.
4. sports performance As a dietary supplement ingredient, Simulin is often claimed to improve energy levels, alertness, and fat oxidation rates during exercise, but the strength of relevant clinical evidence varies and there are individual differences.
5. Cardiovascular effects This is the focus of security concerns for Xin Flynn. Compared with ephedrine, sinomenine has a relatively stronger excitatory effect on alpha receptors, while its direct effect on beta 1- and beta 2- receptors is weaker. This may lead to peripheral vascular constriction, causing a mild increase in blood pressure, while the direct impact on heart rate may be relatively small. However, in sensitive individuals or at high doses, adverse reactions such as palpitations and elevated blood pressure may still occur.

Mechanism of action and molecular targets

The weight loss effect of sinomenine involves a complex regulatory network with multiple targets and pathways, and its core mechanism revolves around the sympathetic nervous system and energy metabolism balance.

1. Adrenergic receptor activation Simulin is a non selective agonist of alpha adrenergic receptors (alpha AR) and beta adrenergic receptors (beta AR). Among them, the stimulation of β 3-AR is considered to be the key to its promotion of fat breakdown and heat production. β 3-AR is mainly distributed in white and brown adipose tissue. After activation, it activates adenylate cyclase (AC) through Gs protein, increases intracellular cyclic adenosine monophosphate (cAMP) levels, and subsequently activates protein kinase A (PKA). PKA phosphorylates and activates hormone sensitive lipase (HSL), promoting triglyceride breakdown. In brown adipose tissue, the cAMP/PKA pathway also regulates the expression and activity of coupling protein 1 (UCP1), uncoupling the mitochondrial respiratory chain from ATP synthesis and releasing chemical energy in the form of thermal energy.
2. Regulation of key metabolic targets：
   • AMPK (PRKAA1) activation Simferon may indirectly activate AMP activated protein kinase (AMPK) by affecting cellular energy status. AMPK is a cellular energy receptor that, when activated, can inhibit the expression of the key transcription factor sterol regulatory element binding protein 1c (SREBF1) and its downstream target genes such as fatty acid synthase (FASN), while promoting fatty acid oxidation.
   • PPARG inhibition Peroxisome proliferator activated receptor gamma (PPARG) is the main regulator of adipocyte differentiation and lipid storage. Research has shown that sinomenine may inhibit the transcriptional activity of PPARG, thereby suppressing the differentiation of preadipocytes into mature adipocytes and reducing fat storage.
   • Fat factor related targets Simulin may affect the leptin (LEP) signaling pathway. In theory, it indirectly acts on the leptin receptor (LEPR) by reducing fat mass or improving leptin sensitivity. In addition, it may also have a regulatory effect on fatty acid binding protein 4 (FABP4), which is involved in intracellular fatty acid transport.
   • Other potential targets Some studies have suggested that transient receptor potential vanillic acid subtype 1 (TRPV1) may mediate partial thermogenic effects of sinomenine, but the specific mechanism remains to be elucidated.

In summary, Simulin exerts a synergistic effect on the adrenergic receptor system (especially β 3-AR) and downstream energy metabolism key nodes (such as AMPK, PPARG, UCP1), forming a network that promotes fat breakdown, inhibits fat synthesis, and increases energy expenditure, thereby combating obesity.

Evaluation of drug properties and pharmacokinetics

Based on the provided parameters and existing research, a preliminary evaluation of the pharmacological properties of sinomenine is conducted

• Absorption and distribution Simulin has good water solubility and moderate LogP, suggesting that its oral absorption may be better. Animal and human pharmacokinetic studies have shown that absorption is rapid after oral administration, with a peak time (Tmax) of approximately 1-3 hours. Its low blood-brain barrier permeability means that the risk of central nervous system side effects is relatively low, which is consistent with its characteristic of mainly acting on peripheral adrenergic receptors.
• Metabolism and excretion Simulin is mainly metabolized in the body through catechol-O-methyltransferase (COMT), monoamine oxidase (MAO), and a combination of sulfation and glucuronidation reactions. The main metabolites include p-hydroxymandelic acid, p-hydroxybenzoic acid, etc. The prototype drug and its metabolites are mainly excreted through the kidneys and urine, with a relatively short half-life of about 2-4 hours.
• Preliminary evaluation of safety：
  • HERG inhibition The data shows' no ', indicating that sinomenine may not significantly inhibit hERG potassium channels at conventional doses, and the risk of cardiac toxicity induced by apical torsion ventricular tachycardia is low.
  • Genotoxicity The Ames test result is 0.6 (usually expressed as the ratio of the number of revertant mutant colonies to the control, and specific determination depends on laboratory standards), which needs to be comprehensively evaluated in conjunction with more genetic toxicity tests (such as micronucleus test, chromosome aberration test). Most existing studies suggest that sinomenine has no significant genetic toxicity at recommended doses.
  • Main safety concerns Still due to its impact on the cardiovascular system. Although it has a weak effect on β 1 receptors, the vasoconstriction caused by α - receptor activation may lead to elevated blood pressure, especially when combined with other stimulants such as caffeine, which may have a synergistic effect and increase the risk of hypertension, tachycardia, palpitations, and other conditions. There have been sporadic cases of liver toxicity reported, but the causal relationship is still unclear.

Clinical application prospects and prospects

Simulin, as a natural weight loss supplement, has both clinical application prospects and challenges.

Current applications and potential：
1. Dietary supplement market Simulin is a common ingredient in current weight loss dietary supplements, often combined with caffeine, green tea extract, etc., claiming to enhance thermogenesis and fat oxidation through synergistic effects.
2. Assisted weight management For individuals with mild to moderate obesity, supplements containing sinomenine may provide additional metabolic boosting effects based on dietary control and exercise, but their weight loss effects when used alone are usually milder.
3. Improvement of metabolic syndrome related indicators In addition to weight loss, preliminary studies suggest that it may have certain benefits in improving blood lipid profiles (such as reducing triglycerides), but more high-quality clinical studies are needed to confirm this.

Challenges and Future Prospects：
1. Clarity and dose-dependent efficacy The existing clinical research results are inconsistent, with some showing slight weight loss effects and others being ineffective. In the future, large-scale, randomized double-blind, placebo-controlled clinical trials are needed to clarify the effective dose range, treatment duration, and differences in efficacy for different populations (such as different BMI and metabolic phenotypes).
2. Long term safety assessment Currently, there is a lack of safety data for long-term (>6 months) use of sinomenine. It is necessary to systematically evaluate its long-term effects on the cardiovascular system (dynamic blood pressure, heart rate variability), liver and kidney function, and metabolism. It is crucial to establish a safe usage guide based on risk benefit ratio.
3. Deep exploration of the mechanism of action In addition to the known adrenergic receptor pathway, the effects of sinomenine on emerging obesity related targets such as gut microbiota, adipose tissue inflammation, and mitochondrial function are worth exploring. The use of omics techniques (transcriptome, metabolome) can comprehensively reveal its functional network.
4. Development of new formulations To improve bioavailability, reduce side effects, and achieve targeted delivery, nanocarriers, liposomes, or sustained-release formulations of sinomenine can be developed. For example, designing delivery systems targeting adipose tissue may enhance local efficacy and reduce systemic exposure risk.
5. Research on rational combination therapy Exploring the scientific compatibility of sinomenine with other natural products or drugs with complementary mechanisms, such as AMPK activators and PPAR modulators, may result in synergistic effects, reduced single drug doses, and side effects.
6. Regulations and Quality Control The regulatory policies regarding Simulin in supplements vary globally. We need to strengthen the quality control of raw materials and products, ensure accurate content and no harmful pollutants (such as heavy metals and pesticide residues), and standardize product labels with clear warning information.

Conclusion

As a natural alkaloid derived from lime, sinomenine exhibits multiple pharmacological potentials by stimulating alpha - and beta adrenergic receptors and regulating key metabolic targets such as AMPK, PPARG, UCP1, etc., promoting fat breakdown, increasing energy expenditure, and regulating lipid metabolism, making it a valuable asset in the field of obesity management. Its pharmacological parameters show that it has good oral absorption characteristics, low central penetration, and low risk of hERG inhibition. However, its clinical application is still limited by challenges such as insufficient evidence of efficacy, potential cardiovascular risks, and lack of long-term safety data. Future research should strive to confirm its efficacy and safety boundaries through rigorous clinical trials, use modern scientific technology to deeply elucidate its multidimensional mechanisms of action, and explore novel delivery systems and rational combination strategies. Only under the premise of science and regulations can Simulin, a natural product, better realize its potential value and provide a relatively safe and effective supplementary option for global obesity prevention and control.