Anagyrine

Last updated
Anagyrine
Anagyrine.svg
Skeletal structure of anagyrine
Anagyrine-based-on-xtal-3D-bs-17.png
Names
Systematic IUPAC name
(7Ξ,7aR,14Ξ)-7,7a,8,9,10,11,13,14-Octahydro-4H,6H-7,14-methanodipyrido[1,2-a:1′,2′-e][1,5]diazocin-4-one
Other names
Rhombinine; Anagyrin; Monolupin; Monolupine; Rhombinin; [3] 3,4,5,6-Tetradehydrospartein-2-one; [4] [7R-(7α,7aβ,14α)]-7,7a,8,9,10,11,13,14-Octahydro-7,14-methano-4H,6H-dipyrido[1,2-a:1′,2′-e][1,5]diazocin-4-one [3]
Identifiers
3D model (JSmol)
ECHA InfoCard 100.215.995 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C15H20N2O/c18-15-6-3-5-14-11-8-12(10-17(14)15)13-4-1-2-7-16(13)9-11/h3,5-6,11-13H,1-2,4,7-10H2/t11?,12?,13-/m1/s1
    Key: FQEQMASDZFXSJI-WXRRBKDZSA-N
  • C1CCN2CC3CC(C2C1)CN4C3=CC=CC4=O
Properties
C15H20N2O
Molar mass 244.338 g·mol−1
Density 1.22 ±0.1 g/mL [5]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Anagyrine is a teratogenic alkaloid first isolated from (and named for) Anagyris foetida in the year 1885 by French biologists Hardy and Gallois. [6] A. foetida (family Fabaceae), the Stinking Bean Trefoil, is a highly toxic shrub native to the Mediterranean region, with a long history of use in folk medicine. [7] [8] In the year 1939 Anagyrine was found by James Fitton Couch to be identical to an alkaloid present in many species belonging to the plant genus Lupinus (lupins). [9] The toxin can cause crooked calf disease if a cow ingests the plant during certain periods of pregnancy.

Contents

Background

The toxicity of certain species of Lupinus plants has been known for several years. The plant is very common in western North America and is sometimes used in feed for cattle if the toxicity of the given lupine is low enough. The toxicity of the plant comes from a variety of toxins, however out of these chemicals anagyrine is the most well known for causing crooked calf disease when ingested by cows. [10] The discovery of anagyrine was made in 1885 by French biologists Ernest Hardy (born Paris 1826) and N. Gallois, who isolated it from the highly toxic legume Anagyris foetida , while the earliest isolation of anagyrine from a lupinus plant was recorded in 1939. [11] [9] The toxin can be found in growing leaf material in a young lupinus plant and in the flower and seed of a mature plant, though varying concentrations of the alkaloid are present throughout lupines that contain anagyrine. [10] The first correlation between anagyrine and crooked calf disease was made by Richard Keeler in 1973. [12] Recently there have been a few successful syntheses of anagyrine recorded, most notably one completed by Diane Gray and Timothy Gallagher. [13]

Toxicity

Anagyrine causes crooked calf disease if 1.44 g/kg of the substance is ingested by the mother cow between days 40 and 70 of pregnancy. Out of the hundreds of varieties of lupinus plants, 23 (listed below) are known to contain high enough concentrations of anagyrine to be dangerous to cattle. [14] [15] The IC50 of anagyrine is 132 μM at muscarinic receptors and 2,096 μM at nicotinic receptors. [16]

Common NameScientific Name
Mountain Silvery Lupine L. alpestris
Arctic Lupine L. arcticus
Anderson's Lupine L. andersonii
Spur Lupine L. arbustus
Silvery Lupine L. argenteus
Tail Cup Lupine L. caudatus
unknown L. cyaneus
Lunara Lupine L. formosus
unknown L. greenei
Broad-Leafed Lupine L. latifolius
Spurred Lupine L. laxiflorus
White-Leaved Lupine L. leucophyllus
Nootka Lupine L. nootaktensis
Plumes Lupine L. onustus
Meadow Lupine L. polyphyllus
Rusty Lupine L. pusillus
Silky Lupine L. sericeus
Yellow Lupine L. sulphureus
Burke's Lupine L. burkei
Seashore Lupine L. littoralis
Pine Lupine L. albicaulis
Tall Silvery Lupine L. erectus
Mt. Rose Lupine L. montigenus

Symptoms

Known symptoms of crooked cow disease include arthrogryposis (permanently flexed joints), torticollis (twisting of the neck), scoliosis (curving of the spine), kyphosis (humpback), and cleft plate. It is thought that teratogenic alkaloids like anagyrine cause the deformities by sedating the fetus, causing it to remain fixed in an abnormal position as it grows. [10] Lasting malformations of the calf can occur even in mild poisonings of the cow because fetal movement depression persists much longer between doses of teratogenic alkaloids than the signs of toxicity in the cow.

Symptoms of the alkaloid being ingested by a cow include dyspnea, nervousness, grounding of teeth, depression, salivation, ataxia, spasms, head pressing tremors, seizures, coma, and sometimes death within days of ingestion. If the cattle do not die as a result of alkaloid ingestion, most make a complete recovery with no lasting signs of being poisoned. [17] [16]

Mechanism of Action

While the specific mechanism of action of anagyrine is unknown, the structure of anagyrine allows it to be mistaken for acetylcholine by certain receptors in living organisms. Anagyrine is thought to act as an acetylcholine agonist, increasing the amount of signal being sent to muscles in the organism's body, much like nicotine. Anagyrine interacts with nicotinic and muscarinic acetylcholine receptors, however it binds to muscarinic receptors 16 times more strongly, making it likely that the blocking of muscarinic acetylcholine receptors is what causes crooked calf disease. [16]

Related Research Articles

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Muscarine</span> Chemical compound

Muscarine, L-(+)-muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. Mushrooms in the genera Entoloma and Mycena have also been found to contain levels of muscarine which can be dangerous if ingested. Muscarine has been found in harmless trace amounts in Boletus, Hygrocybe, Lactarius and Russula. Trace concentrations of muscarine are also found in Amanita muscaria, though the pharmacologically more relevant compound from this mushroom is the Z-drug-like alkaloid muscimol. A. muscaria fruitbodies contain a variable dose of muscarine, usually around 0.0003% fresh weight. This is very low and toxicity symptoms occur very rarely. Inocybe and Clitocybe contain muscarine concentrations up to 1.6%.

A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because acetylcholine (ACh) is the neurotransmitter used by the PSNS. Chemicals in this family can act either directly by stimulating the nicotinic or muscarinic receptors, or indirectly by inhibiting cholinesterase, promoting acetylcholine release, or other mechanisms. Common uses of parasympathomimetics include glaucoma, Sjögren syndrome and underactive bladder.

<span class="mw-page-title-main">Chlorfenvinphos</span> Chemical compound

Chlorfenvinphos is an organophosphorus compound that was widely used as an insecticide and an acaricide. The molecule itself can be described as an enol ester derived from dichloroacetophenone and diethylphosphonic acid. Chlorfenvinphos has been included in many products since its first use in 1963. However, because of its toxic effect as a cholinesterase inhibitor it has been banned in several countries, including the United States and the European Union. Its use in the United States was cancelled in 1991.

<span class="mw-page-title-main">Phytochemistry</span> Study of phytochemicals, which are chemicals derived from plants

Phytochemistry is the study of phytochemicals, which are chemicals derived from plants. Phytochemists strive to describe the structures of the large number of secondary metabolites found in plants, the functions of these compounds in human and plant biology, and the biosynthesis of these compounds. Plants synthesize phytochemicals for many reasons, including to protect themselves against insect attacks and plant diseases. The compounds found in plants are of many kinds, but most can be grouped into four major biosynthetic classes: alkaloids, phenylpropanoids, polyketides, and terpenoids.

<span class="mw-page-title-main">Epibatidine</span> Toxic chemical from some poison dart frogs

Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi and poison dart frogs from the Ameerega genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine.

A cholinergic crisis is an over-stimulation at a neuromuscular junction due to an excess of acetylcholine (ACh), as a result of the inactivity of the AChE enzyme, which normally breaks down acetylcholine.

<span class="mw-page-title-main">Arecoline</span> Mild stimulant

Arecoline is a nicotinic acid-based mild parasympathomimetic stimulant alkaloid found in the areca nut, the fruit of the areca palm. It is an odourless oily liquid. It can bring a sense of enhanced alertness and energy along with mild feelings of euphoria and relaxation. The psychoactive effects are comparable to that of nicotine.

<span class="mw-page-title-main">Lupinine</span> Chemical compound

Lupinine is a quinolizidine alkaloid present in the genus Lupinus of the flowering plant family Fabaceae. The scientific literature contains many reports on the isolation and synthesis of this compound as well as a vast number of studies on its biosynthesis from its natural precursor, lysine. Studies have shown that lupinine hydrochloride is a mildly toxic acetylcholinesterase inhibitor and that lupinine has an inhibitory effect on acetylcholine receptors. The characteristically bitter taste of lupin beans, which come from the seeds of Lupinus plants, is attributable to the quinolizidine alkaloids which they contain, rendering them unsuitable for human and animal consumption unless handled properly. However, because lupin beans have potential nutritional value due to their high protein content, efforts have been made to reduce their alkaloid content through the development of "sweet" varieties of Lupinus.

<span class="mw-page-title-main">Anabasine</span> Chemical compound

Anabasine is a pyridine and piperidine alkaloid found in the Tree Tobacco plant, as well as in the close relative of the common tobacco plant. It is a structural isomer of, and chemically similar to, nicotine. Its principal (historical) industrial use is as an insecticide.

<span class="mw-page-title-main">Methyllycaconitine</span> Chemical compound

Methyllycaconitine (MLA) is a diterpenoid alkaloid found in many species of Delphinium (larkspurs). In common with many other diterpenoid alkaloids, it is toxic to animals, although the acute toxicity varies with species. Early research was focused on identifying, and characterizing the properties of methyllycaconitine as one of the principal toxins in larkspurs responsible for livestock poisoning in the mountain rangelands of North America. Methyllycaconitine has been explored as a possible therapeutic agent for the treatment of spastic paralysis, and it has been shown to have insecticidal properties. Most recently, it has become an important molecular probe for studying the pharmacology of the nicotinic acetylcholine receptor.

<span class="mw-page-title-main">Muscarinic antagonist</span> Drug that binds to but does not activate muscarinic cholinergic receptors

A muscarinic receptor antagonist (MRA) is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the nervous system, and muscarinic receptor antagonists work to prevent this transmission from occurring. Notably, muscarinic antagonists reduce the activation of the parasympathetic nervous system. The normal function of the parasympathetic system is often summarised as "rest-and-digest", and includes slowing of the heart, an increased rate of digestion, narrowing of the airways, promotion of urination, and sexual arousal. Muscarinic antagonists counter this parasympathetic "rest-and-digest" response, and also work elsewhere in both the central and peripheral nervous systems.

<span class="mw-page-title-main">Surugatoxin</span> Chemical compound

Surugatoxin (SGTX) is a type of venom found in the mid-gut digestive gland of the Japanese ivory mollusk Babyloniajaponica, a carnivorous gastropod. It functions as a ganglionic blocker of nicotinic acetylcholine receptors (nAChRs). The structurally and functionally related neosurugatoxin, also derived from Babylonia japonica, is an even more potent nAChR antagonist than SGTX.

<i>Conium maculatum</i> Poisonous herbaceous plant in the carrot family

Conium maculatum, colloquially known as hemlock, poison hemlock or wild hemlock, is a highly poisonous biennial herbaceous flowering plant in the carrot family Apiaceae, native to Europe and North Africa. A hardy plant capable of living in a variety of environments, hemlock is widely naturalised in locations outside its native range, such as parts of Australia, West Asia, and North and South America, to which it has been introduced. It is capable of spreading and thereby becoming an invasive weed.

<i>Lupinus formosus</i> Species of legume

Lupinus formosus, the summer lupine or western lupine, is a species of flowering plant in the legume family, Fabaceae. It is native to California and Oregon in the United States.

<i>Lupinus leucophyllus</i> Species of legume

Lupinus leucophyllus is a species of lupine known by the common name velvet lupine. It is native to western North America, where it grows in many types of mountain, prairie, and plateau habitat. It is a robust, branching, erect perennial herb growing up to 90 centimetres (35 in) tall. Each palmate leaf is divided into 7 to 11 leaflets up to 7 centimetres (2.8 in) long. The herbage is coated in white woolly fibers and stiff hairs. The inflorescence is dense raceme of many flowers, each around a centimeter long. The flower is purple in color, fading brown, the patch on the banner petal yellow or brownish. The pointed sepals and the back of the banner are hairy to woolly in texture.

<i>Lupinus sericeus</i> Species of legume

Lupinus sericeus is a species of flowering plant in the legume family known by the common name silky lupine or Pursh's silky lupine. It is native to western North America from British Columbia to Arizona and east to Alberta and Colorado.

<span class="mw-page-title-main">Quinolizidine alkaloids</span>

Quinolizidine alkaloids are natural products that have a quinolizidine structure; this includes the lupine alkaloids.

<span class="mw-page-title-main">Cholinergic blocking drug</span> Drug that block acetylcholine in synapses of cholinergic nervous system

Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.

<i>Anagyris foetida</i> Species of plant

Anagyris foetida, is a species of flowering plant in the family Fabaceae, forming a malodorous, Summer-deciduous shrub or small tree 2-4m in height with green twigs bearing grey-green trifoliate leaves clad beneath in silvery hairs. The red-tinged, yellow, Laburnum-like flowers are borne on the previous season's growth and are pollinated mainly by birds and bees - notably the buff-tailed bumblebee.The large spot of red pigmentation on the flowers is located on the exterior of the standard, the interior of which bears, in turn, many small, deep red spots.

References

  1. Turgunov, K.K.; Rakhimov, S.B.; Vinogradova, V.I.; Tashkhodjaev, B. (2015). "CSD Entry: UHUHOW". Cambridge Structural Database: Access Structures. Cambridge Crystallographic Data Centre. doi:10.5517/cc14ll5h . Retrieved 2022-07-28.
  2. Turgunov, K. K.; Rakhimov, S. B.; Vinogradova, V. I.; Tashkhodjaev, B. (2015). "Crystal structure of anagyrine perchlorate". Acta Crystallogr. E . 71 (5): o343–o344. Bibcode:2015AcCrE..71O.343T. doi: 10.1107/S2056989015007781 . PMC   4420039 . PMID   25995939. S2CID   22686042.
  3. 1 2 P.J. Linstrom and W.G. Mallard, Eds., NIST Chemistry WebBook, NIST Standard Reference Database Number 69, National Institute of Standards and Technology, Gaithersburg MD, 20899, doi:10.18434/T4D303, (retrieved April 21, 2017)
  4. "3,4,5,6-Tetradehydrospartein-2-one." 3,4,5,6-Tetradehydrospartein-2-one | C15H20N2O | ChemSpider. Royal Society of Chemistry, n.d. Web. 25 Apr. 2017.
  5. 486-89-5(ANAGYRINE) Product Description." ChemicalBook---Chemical Search Engine. N.p., n.d. Web. 21 Apr. 2017.
  6. Hardy and Gallois, Comptes-rendus et Mémoires de la Société de Biologie , 13th June 1885
  7. Pedanius Dioscorides, De materia medica Book 3: "Roots of Akanthoda (= Prickly Plants) No. 167 "Anaguris [Onaguris]" http://www.cancerlynx.com/BOOKTHREEROOTS.PDF
  8. Partheil and Spassky, Apoth. Ztg. 1895, 10, 903 https://pubs.rsc.org/en/Image/Get?imageInfo.ImageType=GA&imageInfo.ImageIdentifier.ManuscriptID=JR9330000504&imageInfo.ImageIdentifier.Year=1933 Retrieved at 11.59 on 28/11/22.
  9. 1 2 Couch, James Fitton. "Lupine Studies. XIV.1 The Isolation of Anagyrine FromLupinus Laxiflorusvar.silvicola C. P. Smith." Journal of the American Chemical Society 61.12 (1939): 3327-328. https://pubs.acs.org/doi/pdf/10.1021/ja01267a027 Retrieved at 12.18 on 28/11/22.
  10. 1 2 3 "AAHP Field Disease Investigation Unit (FDIU)." Crooked Calf. Washington State University: College of Veterinary Medicine, 2015. Web. 23 Apr. 2017.
  11. Hardy, E., and N. Gallois. "Keeler, Richard F. "Lupin Alkaloids from Teratogenic and Nonteratogenic Lupins. I. Correlation of Crooked Calf Disease Incidence with Alkaloid Distribution Determined by Gas Chromatography." Teratology 7.1 (1973): 23-30. Wiley Online Library. Web." The Journal of the Chemical Society 54 (1888): n. pag. Abstract. The Journal of the Chemical Society (n.d.): n. pag. Print.
  12. Keeler, Richard F. "Lupin Alkaloids from Teratogenic and Nonteratogenic Lupins. I. Correlation of Crooked Calf Disease Incidence with Alkaloid Distribution Determined by Gas Chromatography." Teratology 7.1 (1973): 23-30. Wiley Online Library. Web.
  13. Gray, Diane, and Timothy Gallagher. "A Flexible Strategy for the Synthesis of Tri- and Tetracyclic Lupin Alkaloids: Synthesis of ( )-Cytisine, (±)-Anagyrine, and (±)-Thermopsine." Angewandte Chemie International Edition 45.15 (2006): 2419-423. Web.
  14. Davis, A. M., and D. M. Stout. "Anagyrine in Western American Lupines." Journal of Range Management 1.39 (1986): n. pag. Web. 23 Apr. 2017.
  15. Gupta, Ramesh C. Veterinary Toxicology: Basic and Clinical Principles. N.p.: Academic, 2007. Print.
  16. 1 2 3 GUPTA, RAMESH C. Reproductive and Developmental Toxicology. Place of Publication Not Identified: ELSEVIER ACADEMIC, 2017. Print.
  17. Schenck, Patricia. Saunders Comprehensive Review of the Navle: Pageburst Retail. Place of Publication Not Identified: Elsevier Saunders, 2009. Print.