Names | |
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IUPAC name 4β,12,14,16β,17,20-Hexahydroxy-4α,9-epoxycevan-3β-yl 3,4-dimethoxybenzoate | |
Systematic IUPAC name (3S,4S,4aS,6aS,6bR,8S,8aS,9R,9aS,12S,15aS,15bR,16aR,16bS)-4,6b,8,8a,9,15b-Hexahydroxy-9,12,16b-trimethyldocosahydro-2H-4,16a-epoxybenzo[4,5]indeno[1,2-h]pyrido[1,2-b]isoquinolin-3-yl 3,4-dimethoxybenzoate | |
Other names (3β,4β,16β)-4,12,14,16,17,20-Hexahydroxy-4,9-epoxycevan-3yl 3,4-dimethoxybenzoate 3-Veratroylveracevine | |
Identifiers | |
3D model (JSmol) | |
ChEMBL | |
ChemSpider | |
ECHA InfoCard | 100.000.690 |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C36H51NO11 | |
Molar mass | 673.800 g·mol−1 |
Melting point | 160 to 180 °C (320 to 356 °F; 433 to 453 K) |
Hazards | |
Occupational safety and health (OHS/OSH): | |
Main hazards | Toxic |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Veratridine is a steroidal alkaloid found in plants of the lily family, specifically the genera Veratrum and Schoenocaulon . [1] Upon absorption through the skin or mucous membranes, it acts as a neurotoxin by binding to and preventing the inactivation of voltage-gated sodium ion channels in heart, nerve, and skeletal muscle cell membranes. [2] Veratridine increases nerve excitability and intracellular Ca2+ concentrations.
Veratridine has been isolated from the seeds of Schoenocaulon officinale and from the rhizomes of Veratrum album. Like the other steroidal alkaloids found in these plants and similar ones in the Melanthiaceae family, it is present as part of a glycosidal combination, bonded to carbohydrate moieties. [1]
Early isolation methods relied on formation of the nitrate salt and then precipitation of the insoluble sulfate form. [3] Accounts of these efforts date back to 1878, but the first true purification of veratridine is the one carried out in 1953 by Kupchan et al. This, and later purification procedures, begin with veratrine, a mixture of the alkaloids present in the Veratrum plants, primarily containing cevadine and veratridine. The nitrate salt is formed by dissolving the veratrine in 1% sulfuric acid over ice and precipitating with sodium nitrate. After resuspending in water over ice, the solution is brought to pH 8.5 with aqueous NaOH and then pH 10 with aqueous ammonia, forming another precipitate which is extracted with ether and then with chloroform. The ether and chloroform fractions are combined and dried. The dried residue is dissolved in sulfuric acid and the sulfate salt of veratridine is precipitated by dropwise addition of a solution of ammonium sulfate. Finally, the free base form is generated with ammonium hydroxide. [4]
An even better isolation of veratridine from veratrine is achieved using high-performance liquid chromatography (HPLC); as commercially available veratridine may vary in purity, HPLC purification of veratrine is a preferred method for isolation of veratridine for biological studies. [3]
Veratridine is a derivative, the 3-veratroate ester, of veracevine, which belongs to the class of C-nor-D-homosteroidal alkaloids. The molecular structure and stereochemistry of this and related alkaloids were only established after decades of chemical investigations. [5] The structure of veratridine has been confirmed by NMR spectroscopy [6] and X-ray crystallography. [7]
Veratridine displays an unusual steroidal backbone. In the typical four-ring nucleus with three six-membered rings and one five-membered ring (like the one in cholesterol), the five-membered ring is on the end. Veratridine, and other Veratrum alkaloids, have the five-membered ring between the second and third six-membered rings. [1]
Veratridine has a pKa of 9.54. [4] It is slightly soluble in ether, soluble in ethanol and DMSO, and freely soluble in chloroform. [8] Solubility in water is pH-dependent; the free base form is slightly soluble, but easily dissolves in 1 M HCl. [8] Its nitrate salt is slightly soluble in water. [9] Its sulfate salt is very hygroscopic. [9]
Veratridine acts a neurotoxin by increasing nerve excitability. It binds to binding site 2 on the voltage-gated sodium channels (the same site bound by batrachotoxin, aconitine, and grayanotoxin), leading to persistent activation. [10] Veratridine inhibits sodium channel inactivation by shifting the activation threshold toward a more negative potential. The resulting influx of Na+ also leads to the increase of intracellular Ca2+ concentrations, causing the overproduction of reactive oxygen species responsible for neuronal damage. [11]
Veratridine is readily absorbed through the skin and mucous membranes and through ingestion. The tissues most affected are the heart, nerves, and skeletal muscles: [2] main symptoms of veratridine toxicity include severe nausea, bradycardia, hypotension, difficulty breathing, salivation, and muscle weakness. [12] Treatment involves the administration of activated charcoal, atropine, and benzodiazepines (if the affected individual is seizing). [12]
Veratridine's ability to depolarize cells by affecting sodium channels lends it its applicability as a neuropharmacological tool for the study of electrical properties of nerve and muscle fibers. [3] It has also been tested as a treatment for myasthenia gravis, in light of its potential to increase muscle responses to motor neuron stimulation. [12]
Furthermore, this compound has recently been reported to increase sperm progressive motility (although it does not produce hyperactivation by itself). It has the potential of enhancing protein tyrosine phosphorylation, which takes place during capacitation, and its effects are inhibited in the presence of lidocaine and tetrodotoxin.
Veratridine has not been reported to have any effect on the acrosome reaction on its own, but it is able to block the progesterone-induced acrosome reaction. Moreover, veratridine has the effect of turning the membrane potential to a more positive one and also modifies the effect of progesterone on [Ca2+]i and sperm membrane potential.
The activation of Nav1.8 is a key point in Veratradine's mechanism of action and, consequently, this sodium ion channel coordinates the effects of this compound. Veratradine also activates additional Nav channels. These facts contribute to support the importance of these Veratradine-sensitive proteins in the regulation of mature sperm function, such as human sperm fertility acquisition regulating motility, capacitation and the progesterone-induced acrosome reaction. [13]
Aconitine is an alkaloid toxin produced by various plant species belonging to the genus Aconitum, known also commonly by the names wolfsbane and monkshood. Monkshood is notorious for its toxic properties.
The acrosome is an organelle that develops over the anterior (front) half of the head in the spermatozoa of humans, and many other animals. It is a cap-like structure derived from the Golgi apparatus. In placental mammals the acrosome contains degradative enzymes. These enzymes break down the outer membrane of the ovum, called the zona pellucida, allowing the haploid nucleus in the sperm cell to join with the haploid nucleus in the ovum. This shedding of the acrosome, or acrosome reaction, can be stimulated in vitro by substances a sperm cell may encounter naturally such as progesterone or follicular fluid, as well as the more commonly used calcium ionophore A23187. This can be done to serve as a positive control when assessing the acrosome reaction of a sperm sample by flow cytometry or fluorescence microscopy. This is usually done after staining with a fluoresceinated lectin such as FITC-PNA, FITC-PSA, FITC-ConA, or fluoresceinated antibody such as FITC-CD46.
The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is also a secondary site of androgen synthesis.
A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.
Batrachotoxin (BTX) is an extremely potent cardio- and neurotoxic steroidal alkaloid found in certain species of beetles, birds, and frogs. The name is from the Greek word βάτραχος, bátrachos, 'frog'. Structurally-related chemical compounds are often referred to collectively as batrachotoxins. In certain frogs, this alkaloid is present mostly on the skin. Such frogs are among those used for poisoning darts. Batrachotoxin binds to and irreversibly opens the sodium channels of nerve cells and prevents them from closing, resulting in paralysis and death. No antidote is known.
Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.
Ion exchange is a reversible interchange of one kind of ion present in an insoluble solid with another of like charge present in a solution surrounding the solid with the reaction being used especially for softening or making water demineralised, the purification of chemicals and separation of substances.
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocorticoids. In addition, pregnenolone is biologically active in its own right, acting as a neurosteroid.
Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Ca2+ can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.
The cation channels of sperm also known as Catsper channels or CatSper, are ion channels that are related to the two-pore channels and distantly related to TRP channels. The four members of this family form voltage-gated Ca2+ channels that seem to be specific to sperm. As sperm encounter the more alkaline environment of the female reproductive tract, CatSper channels become activated by the altered ion concentration. These channels are required for proper fertilization. The study of these channels has been slow because they do not traffic to the cell membrane in many heterologous systems.
Taicatoxin (TCX) is a snake toxin that blocks voltage-dependent L-type calcium channels and small conductance Ca2+-activated K+ channels. The name taicatoxin (TAIpan + CAlcium + TOXIN) is derived from its natural source, the taipan snake, the site of its action, calcium channels, and from its function as a toxin. Taicatoxin was isolated from the venom of Australian taipan snake, Oxyuranus scutellatus scutellatus. TCX is a secreted protein, produced in the venom gland of the snake.
Veratrum album, the false helleborine, white hellebore, European white hellebore, or white veratrum is a poisonous plant in the family Melanthiaceae. It is native to Europe and parts of western Asia.
Pumiliotoxin 251D is a toxic organic compound. It is found in the skin of poison frogs from the genera Dendrobates, Epipedobates, Minyobates, and Phyllobates and toads from the genus Melanophryniscus. Its name comes from the pumiliotoxin family (PTXs) and its molecular mass of 251 Daltons. When the toxin enters the bloodstream through cuts in the skin or by ingestion, it can cause hyperactivity, convulsions, cardiac arrest and ultimately death. It is especially toxic to arthropods, even at low concentrations.
Sperm guidance is the process by which sperm cells (spermatozoa) are directed to the oocyte (egg) for the aim of fertilization. In the case of marine invertebrates the guidance is done by chemotaxis. In the case of mammals, it appears to be done by chemotaxis, thermotaxis and rheotaxis.
Huwentoxins (HWTX) are a group of neurotoxic peptides found in the venom of the Chinese bird spider Haplopelma schmidti. The species was formerly known as Haplopelma huwenum, Ornithoctonus huwena and Selenocosmia huwena. While structural similarity can be found among several of these toxins, HWTX as a group possess high functional diversity.
Steroidal alkaloids have the basic steroidal skeleton with nitrogen-based functional groups attached to the skeleton. More specifically, they are distinguished by their tetracyclic cyclopentanoperhydrophenanthrene skeleton that marks their close relationship with sterols. They fall in two major categories: Solanum alkaloids and Veratrum alkaloids. A Steroidal alkaloid has also been found in Chonemorpha fragrans, 'chonemorphine' was used to treat intestinal infections in Wistar rats..
Dioscorine is an alkaloid toxin isolated from the tubers of tropical yam on several continents. It has been used as a monkey poison in some African countries, and as an arrow poison to aid in hunting in several parts of Asia. It was first isolated from Dioscorea hirsute by Boorsma in 1894 and obtained in a crystalline form by Schutte in 1897, and has since been found in other Dioscorea species. Dioscorine is a neurotoxin that acts by blocking the nicotinic acetylcholine receptor. Dioscorine is generally isolated in tandem with other alkaloids such as dioscin but is usually the most potent toxin in the mixture. It is a convulsant, producing symptoms similar to picrotoxin, with which it shares a similar mechanism of action.
Gambierol is a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Gambierol is collected from the sea at the Rangiroa Peninsula in French Polynesia. The toxins are accumulated in fish through the food chain and can therefore cause human intoxication. The symptoms of the toxicity resemble those of ciguatoxins, which are extremely potent neurotoxins that bind to voltage-sensitive sodium channels and alter their function. These ciguatoxins cause ciguatera fish poisoning. Because of the resemblance, there is a possibility that gambierol is also responsible for ciguatera fish poisoning. Because the natural source of gambierol is limited, biological studies are hampered. Therefore, chemical synthesis is required.
Zygacine is a steroidal alkaloid of the genera Toxicoscordion, Zigadenus, Stenanthium and Anticlea of the family Melanthiaceae. These plants are commonly known and generally referred to as death camas. Death camas is prevalent throughout North America and is frequently the source of poisoning for outdoor enthusiasts and livestock due to its resemblance to other edible plants such as the wild onion. Despite this resemblance, the death camas plant lacks the distinct onion odor and is bitter to taste.
Goniopora toxin (GPT) is a polypeptide toxin from the marine Goniopora species coral. Two toxins from this source have been identified, one acting on sodium channels and one acting on calcium channels.