Tetramethylpyrazine

Description

Tetramethylpyrazine (TMP) is a kind of alkaloids identified in Ligusticum wallichii FRANCH. It has various kinds of medical applications. It has long been used in China for the treatment of cardiovascular problems. It also has antiinflammatory and analgesic effect. It can be used for the treatment of diabetic peripheral neuropathy. Through effectively penetrating across the blood-brain barrier, it can exert its neuroprotection function which is useful for the treatment of ischemic brain injury. Moreover, it can eliminate superoxide anion and decreases nitric oxide production in human polymorphonuclear leukocytes.

Chemical Characteristic

White crystal or powder. With aroma of beef and heated lard and fermented soybean flavor. It smells chocolate flavor when diluted to 20mg/kg. Boiling point is 190℃. Melting point is between 84 and 86℃. Soluble in ethanol, most non-volatile oils and propylene glycol, slightly soluble in water.
Natural products exist in guava, roast beef, cocoa, coffee, shrimp and so on.

Uses

• Permissible edible flavors, mainly used to prepare meat, cocoa, peanut, nut, coffee, chocolate flavor and so on;
• For medicine production;
• Used as flavoring agents, sweeteners for alcoholic beverages, flavor and enriching supplement for cigarettes.

Preparation

• Butanedione monoxime generated by butanone and ethyl nitrite condensation is reduced and cyclized to produce methylpyrazine. The cyclization reaction product is subjected to steam distillation and the distillate is cooled,crystallized and filtered to generate crude tetramethylpyrazine which is refined with water recrystallization and activated carbon to decolor. Ethanol solution with 15% to 20% hydrogen chloride can be added into acetone to prepare hydrochloride salt.
• Condensed by 2,3-butanedione and 2,3-butanediamine.

References

TH Tsai, CC Liang. International Journal of Pharmaceutics, 216. 1-2 (2001)
WU, Zhi-youg, et al. Chinese Journal of Experimental Traditional Medical Formulae 14 (2012): 085.
Ozaki, Yukihiro. Chemical and pharmaceutical bulletin 40.4 (1992): 954-956.
Kao, Tsung-Kuei, et al. Neurochemistry international 48.3 (2006): 166-176.
Zhang, Zhaohui, et al. Life sciences 72.22 (2003): 2465-2472.

Description

2,3,5,6-Tetramethylpyrazine is an alkaloid that has been found in L. wallichii and has diverse biological activities. It reduces kainate-induced increases in production of reactive oxygen species (ROS) and cytotoxicity in primary rat hippocampal neurons when used at a concentration of 5 μM. 2,3,5,6-Tetramethylpyrazine (0.1 mM) induces vasodilation in precontracted isolated and endothelium-denuded rat tail artery strips and reduces blood pressure in anesthetized rats. It decreases infarct volume, caspase-3 activation, and hypoxia-inducible factor-1α (HIF-1α) levels in a rat model of focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) when administered at a dose of 20 mg/kg.

Description

Ligustrazine is an alkaloid derived from chuanxiong (Ligusticum chuanxiong Hort; L. wallichii). Ligusticum wallichii Franchat (or Ligusticum chuanxiong Hort; L. wallichii), a member of the Umbelliferaceae family, is a Chinese medicinal herb that is a common constituent in polypharmaceutical herbal drugs. It has been widely used in Asian countries to increase coronary blood flow and systemic circulation and to relieve stasis.
Ligusticum walliichi has the effects of promoting Qi and nourishing blood. Ligusticum walliichi, angelica, and peony were used as medicinal herbs, and thecommonly used Yangxue Siwu decoction was proposed for clinical practice. The combination of gypsum and Ligusticum walliichi can clear lung heat and eliminate cough and asthma. It is a common drug for clearing away heat and toxic substances and purging fire. The compatibility of Ligusticum walliichi and Radix Linderae can regulate the blood and Qi and treat women’s headaches and colds and retrograde and other related pains.
Ligusticum walliichi is warm, acrid, and bitter. It can regulate the blood and conduct Qi, which is commonly used in oral administration. Ligusticum walliichi is used to treat apoplexy, headache, cold pain, the upper reaches of the wind, tears clogging of nose by cold, and so on. At present, the study of Chuanxiong in China and abroad has occurred at the molecular level .

Chemical Properties

2,3,5,6-Tetramethylpyrazine has musty, fermented, coffee odor

Chemical Properties

white crystals or powder

Physical properties

Appearance: colorless needle crystal. Solubility: soluble in hot water, petroleum ether, chloroform, dilute hydrochloric acid, slightly soluble in ether, insoluble in cold water. Melting point: 77–80°C. Boiling point: 190°C. Flash point: 128– 130°C/200mm. Ligustrazine has a particular odor, moisture absorption, and sublimation.

Occurrence

Reported found in French fried potato, bell pepper, wheat bread, emmental cheese, Swiss cheese, Camembert cheese, Gruyere cheese, boiled and cooked beef, grilled and roasted beef, fried beef, cooked lamb and mutton, lamb and mutton liver, grilled and roasted uncured pork, beer, black tea, green tea. Also reported present in cocoa products, coffee, dairy products, oatmeal, galbanum oil, roasted peanuts, soybean, beans, mushroom, trassi, coriander seed, rice bran, trassi, sukiyaki, soy sauce, malt, licorice, dried bonito, wild rice, shrimp, crab, clam, scallop, filberts, rum, sake, wine, whiskey, burley tobacco and soy products.

History

Ligusticum walliichi has a long medicinal history in China and is used in the treatment of headache, promoting blood and Qi circulation, curing chills and alleviating pain”. Clinically, it is mainly used for the treatment of cardiovascular and cerebrovascular diseases. Ligustrazine (2,3,5,6-tetramethylpyrazine) is the main active ingredient of Ligusticum walliich. It was first isolated in 1962 .
In recent years, studies have found that ligustrazine can inhibit the activity of the cerebral cortex and medullary respiratory center, excite vasomotors, induce the expansion of peripheral blood vessels, promote the blood flow of the coronary artery and lower limbs, and reduce blood pressure. Ligustrazine can also paralyze the nerve center and has sedative and analgesic effects.
Studies have suggested that ligustrazine has a variety of new effects, including improving leptomeningeal and peripheral microcirculation and increasing cerebral blood flow, and its effect is better than that of papaverine. Ligustrazine can also protect against experimental cerebral ischemia and alleviate brain edema and the deposition of fibrin in microvessels. Ligustrazine is also used in the treatment of pulmonary heart disease, heart failure, dilated heart disease, portal hypertension, type II diabetes mellitus, tumor and coronary heart disease, and restenosis after stent implantation .

Uses

etramethylpyrazine is an anti-inflammatory compound isolated from the fermented food natto. Tetramethylpyrazine demonstrated in vivo nootropic activity in rats.

Uses

Usually used in research and treatment of multiple disorders.

Uses

2,3,5,6-Tetramethylpyrazine may be used as an analytical reference standard for the quantification of the analyte in Ephedrae herba and Ephedra sinica Stapf using different chromatography techniques.

Preparation

From2,5-dimethylpyrazine by ring alkylationwithMeLi; also by condensation of 2,3-butanedionewith 2,3-butanediamine.

Indications

Ligustrazine is used for occlusive vascular diseases, cerebral thrombosis, vasculitis, coronary heart disease, angina pectoris, and others

Definition

ChEBI: A member of the class of pyrazines that is pyrazine in which all four hydrogens have been replaced by methyl groups. An alkaloid extracted from Chuanxiong (Ligusticum wallichii).

Aroma threshold values

Detection: 1 to 10 ppm. Aroma characteristics at 1.0%: slightly musty, nutty, cocoa-like with a vanilla undernote

Taste threshold values

Taste characteristics at 10 ppm: weak, nutty, musty cocoa and chocolate-like with dry coffee nuances.

General Description

2,3,5,6-Tetramethylpyrazine has been isolated from Ephedra sinica. It is useful in the treatment of several disorders such as asthma, heart failure, rhinitis and urinary incontinence. It is a flavor ingredient of tobacco. It forms cocrystal with 4-hydroxybenzoic acid which exhibits supramolecular synthon polymorphism.

Pharmacology

Traditional Chinese medicine has some advantages in comprehensive treatment under multisite, multitarget conditions and overall regulation. Ligustrazine can inhibit phosphodiesterase activity and inhibit platelet aggregation. It has the typical characteristics of a calcium antagonist and can adjust the release of various vasoactive substances against the vasoconstrictive action of the sympathetic nerve, improve microcirculation, reduce red blood cell aggregation, shorten the erythrocyte electrophoresis time, and thereby reduce blood viscosity .
Ligustrazine can inhibit the proliferation of vascular endothelial cells induced by vascular endothelial growth factor, which may be one of the mechanisms by which angiogenesis is inhibited. The mechanism by which ligustrazine inhibits the proliferation of vascular endothelial cells may be through calcium ion retardation, inhibition of cell adhesion molecules, or through the antagonistic or synergistic effects of some growth factors involved in the proliferation and angiogenesis of vascular endothelial cells
Studies have shown that ligustrazine plays a role in resistance to ischemiareperfusion injury and antiapoptotic effects via the phosphatidylinositol 3- kinase/ protein kinase B (PI3K/Akt) pathway. The phosphorylation of endothelial nitric oxide synthase (eNOS) and generation of nitric oxide (NO) are important downstream effectors, which significantly enhance the myocardial protective effects of ligustrazine.
one of the mechanisms of resistance to fibrosis .

Clinical Use

The main clinical formulation of ligustrazine is ligustrazine hydrochloride injection. Ligustrazine hydrochloride injection was used to prevent restenosis following coronary stent implantation and to treat acute coronary syndrome and ischemic stroke. Ligustrazine hydrochloride injection is helpful in alleviating pulmonary hypertension in patients with pulmonary heart disease. The therapeutic effect of ligustrazine hydrochloride injection on severe cholestatic liver cirrhosis caused by chronic heart failure of rheumatic heart disease is remarkable. In addition, ligustrazine is widely used in the treatment of vertigo syndrome, vertebrobasilar insufficiency, tension headache, and so on. It has a good symptomatic-treatment effect .
Ligustrazine is also reported for the treatment of children with viral myocarditis, chronic renal failure, hepatic fibrosis, portal hypertension, tumors, and diabetic nephropathy. Ligustrazine can relieve symptoms rapidly, and its effect is stable and lasting. It has good clinical promotion value .

Safety Profile

Poison by intravenous and intraperitoneal routes. Moderately toxic by ingestion. When heated to decomposition it emits toxic fumes of NOx.