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Human Endogenous Metabolite
(S)-Higenamine hydrobromide is a selective beta-adrenergic receptor (beta-AR) agonist, primarily targeting beta1 and beta2 adrenergic receptors in the heart and lungs, with potential activity at beta3 receptors as well. Upon binding to beta-AR, it activates the G protein-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade. In the heart (beta1), this leads to increased contractility (positive inotropic effect) and heart rate (positive chronotropic effect). In the lungs (beta2), it causes bronchodilation. In blood vessels (beta2), it induces vasodilation, lowering blood pressure. The (S)-enantiomer is the more active form. The compound is also a substrate for MAO and COMT, the same enzymes that metabolize catecholamines. |
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| ln Vitro |
The condensation of dopamine and 4-hydrophenylacetaldehyde, which is mediated by an enzyme, results in (S)-norcoclaurine and initiates the metabolic route that leads to benzylisoquinoline alkaloids. Tyrosine is subjected to decarboxylation, hydroxylation, and deamination to produce both substrates, which are secondary metabolites[1].
In vitro, (S)-Higenamine hydrobromide has been shown to exhibit remarkable chronotropic (heart rate-increasing) and inotropic (contractility-increasing) effects in guinea-pig spontaneously beating right atria, left atria, and trachea preparations, in a dose-dependent manner. These effects are blocked by the beta-adrenergic antagonist propranolol, confirming the mechanism involves beta-AR activation. In isolated rabbit pulmonary artery, higenamine increases neurotransmitter release in the adrenergic nervous system, possibly through enhancement of cAMP levels, in addition to stimulation of presynaptic beta-adrenoceptors. The compound also stimulates lipolysis and thermogenesis in adipocytes via beta-AR activation. In neuroblastoma cells, it has been shown to have neuroprotective effects. The compound has an IC₅0 of approximately 1-10 uM for beta-AR activation in different tissue preparations. |
| ln Vivo |
In vivo, (S)-Higenamine hydrobromide has been studied in animal models for its potential in treating heart failure, asthma, and bradycardia. In rats and dogs, intravenous administration of higenamine (0.01-1 mg/kg) increases cardiac output, heart rate, and contractility, and lowers blood pressure (via vasodilation). In guinea-pig models of asthma, inhaled or intravenous higenamine produces bronchodilation, comparable to salbutamol. In heart failure models, higenamine improves cardiac function (increased ejection fraction, reduced left ventricular end-diastolic pressure). The compound is rapidly metabolized, and its hemodynamic effects are short-lived (15-30 minutes). (S)-Higenamine is also a prohibited substance in sports; its detection in urine of athletes may result in anti-doping rule violations.
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| Enzyme Assay |
For non-cellular assays (receptor binding), beta-adrenergic receptor binding affinity is measured using radioligand displacement assays. Membranes from cells expressing human beta1 or beta2 receptors (e.g., CHO cells) are incubated with [3H]-CGP-12177 (a beta-AR antagonist, 0.1-1 nM) and various concentrations of (S)-Higenamine (0.1 nM-100 uM) for 60-90 minutes at 25degC. Non-specific binding is determined with 1 uM propranolol. Bound radioactivity is separated by filtration through GF/B filters and measured by scintillation counting. The Ki (inhibition constant) is calculated from IC₅0 values. For cAMP accumulation assays, membranes or whole cells are incubated with (S)-Higenamine, and cAMP levels are measured by competitive ELISA or TR-FRET. For GTPgammaS binding assays, [3⁵S]GTPgammaS binding to G proteins is measured.
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| Cell Assay |
For cell-based assays, CHO-K1 cells stably expressing human beta1 or beta2 receptors are seeded in 96-well plates (2×10⁴ cells/well) in DMEM with 10% FBS. After 24 hours, cells are treated with (S)-Higenamine (0.1 nM-100 uM) for 15-30 minutes. cAMP levels in cell lysates are measured using a cAMP ELISA or HTRF kit. The EC₅0 for cAMP accumulation is calculated. For functional assays in cardiomyocytes, neonatal rat ventricular myocytes (NRVMs) are isolated and seeded in 6-well plates (1×10⁶ cells/well). After 24 hours, cells are treated with (S)-Higenamine (0.1-10 uM). Cell contraction is measured using a video-based edge-detection system. For bronchodilation studies, human bronchial smooth muscle cells (BSMCs) are seeded in 24-well plates, contracted with carbachol (1 uM), then treated with (S)-Higenamine (0.1-10 uM), and relaxation is measured by microscopic observation of cell shortening. Cell viability is assessed by MTT assay.
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| Animal Protocol |
For in vivo animal experiments, rodent models (rats, mice, guinea pigs) are used. For cardiovascular studies, male Sprague-Dawley rats (250-300 g) are anesthetized. (S)-Higenamine hydrobromide is dissolved in saline and administered intravenously (0.01-1 mg/kg). Blood pressure (carotid artery cannula) and heart rate (ECG) are continuously monitored. Cardiac output is measured by thermodilution. For bronchodilation studies, guinea pigs are anesthetized, and bronchial resistance is measured by whole-body plethysmography. (S)-Higenamine (0.1-1 mg/kg) is administered intravenously or by inhalation (nebulized solution, 0.1-1%). Bronchoconstriction is induced by histamine (30 ug/kg, IV) or acetylcholine (50 ug/kg, IV). For heart failure studies, rats with coronary artery ligation-induced heart failure are used. (S)-Higenamine (0.1-1 mg/kg/day) is administered intraperitoneally or by osmotic minipump for 7-14 days. Cardiac function is assessed by echocardiography. For pharmacokinetic studies, blood samples are collected at multiple time points after administration.
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| ADME/Pharmacokinetics |
(S)-Higenamine hydrobromide has a molecular weight of 352.22. The free base (higenamine) has a molecular formula of C16H17NO3 and MW 271.31. The compound is a white to off-white powder, soluble in DMSO (10 mg/mL) and water (5 mg/mL, with sonication). For in vivo formulations, 5% DMSO + 45% PEG300 + 50% water is recommended. The compound should be stored as a powder at -20degC for up to 3 years, and in solution at -80degC for up to 6 months or at -20degC for up to 1 month. (S)-Higenamine is the (S)-(−)-enantiomer; the racemic mixture and (R)-enantiomer have lower activity. The compound contains a catechol structure, making it susceptible to oxidation. Solutions should be prepared fresh and protected from light and air. The hydrobromide salt improves water solubility and stability.
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| Toxicity/Toxicokinetics |
(S)-Higenamine hydrobromide has moderate acute toxicity. The intravenous LD₅0 in rodents is approximately 10-30 mg/kg. At therapeutic doses (0.01-1 mg/kg), side effects are minimal and include mild tachycardia, palpitations, and headache. At higher doses, significant tachycardia, cardiac arrhythmias, and hypotension may occur. Due to its beta-agonist activity, the compound is contraindicated in patients with uncontrolled hypertension, tachyarrhythmias, or hypertrophic cardiomyopathy. The compound is a prohibited substance in sports. Standard laboratory safety precautions for handling adrenergic agonists should be followed (use of PPE, avoid inhalation/ingestion). In case of overdose, beta-blockers (e.g., propranolol) may be used as antidotes. No long-term carcinogenicity studies have been reported.
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| References | |
| Additional Infomation |
(S)-Higenamine hydrobromide is a research compound and is not an FDA-approved drug. It has not undergone Phase III clinical trials for therapeutic use, although preclinical studies suggest potential for heart failure, asthma, and bradycardia. The compound is prohibited by the World Anti-Doping Agency (WADA) and is included on its Prohibited List as a non-specified stimulant (beta-2 agonist) in sports. In traditional Chinese medicine, higenamine-containing plants (Aconitum species) have been used for centuries as cardiotonics and for the treatment of shock and cardiovascular conditions. (S)-Higenamine hydrobromide is used as a research tool to study beta-adrenergic receptor signaling, cardiovascular physiology, bronchodilation, and metabolic regulation (lipolysis, thermogenesis). It is also used as a reference standard for doping control analysis (detection of higenamine in athlete urine samples by LC-MS/MS). Available for research use only. NOT FOR HUMAN THERAPEUTIC USE.
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| Molecular Formula |
C16H18BRNO3
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| Molecular Weight |
352.22
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| Exact Mass |
351.046
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| CAS # |
105990-27-0
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| Related CAS # |
Higenamine hydrochloride;11041-94-4;Higenamine;5843-65-2;(S)-Higenamine;22672-77-1
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| PubChem CID |
12313508
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
21
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| Complexity |
317
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CN[C@H](C2=CC(=C(C=C21)O)O)CC3=CC=C(C=C3)O.Br
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| InChi Key |
KNUKFIRMGSQPEM-UQKRIMTDSA-N
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| InChi Code |
InChI=1S/C16H17NO3.BrH/c18-12-3-1-10(2-4-12)7-14-13-9-16(20)15(19)8-11(13)5-6-17-14;/h1-4,8-9,14,17-20H,5-7H2;1H/t14-;/m0./s1
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| Chemical Name |
(1S)-1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrobromide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8391 mL | 14.1957 mL | 28.3913 mL | |
| 5 mM | 0.5678 mL | 2.8391 mL | 5.6783 mL | |
| 10 mM | 0.2839 mL | 1.4196 mL | 2.8391 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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