Anagyrine is a

teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by ...

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

first isolated from (and named for) ''

Anagyris foetida ''Anagyris foetida'' (English common name stinking bean trefoil), is a species of flowering plant in the family Fabaceae, forming a malodorous, Summer-deciduousPhytognosis http://regenerag.org/blog/2018/4/12/anagyris-foetida-an-underutilized-med ...

'' in the year 1885 by French biologists Hardy and Gallois. ''A. foetida'' (family

Fabaceae Fabaceae () or Leguminosae,International Code of Nomen ...

), the Stinking Bean Trefoil, is a highly toxic shrub native to the Mediterranean region, with a long history of use in

folk medicine Traditional medicine (also known as indigenous medicine or folk medicine) refers to the knowledge, skills, and practices rooted in the cultural beliefs of various societies, especially Indigenous groups, used for maintaining health and treatin ...

. 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 ''Lupinus'', commonly known as lupin, lupine, or regionally bluebonnet, is a genus of plants in the legume family Fabaceae. The genus includes over 199 species, with centre of diversity, centres of diversity in North America, North and South A ...

'' (lupins).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. The toxin can cause crooked calf disease if a cow ingests the plant during certain periods of pregnancy.

Background

The toxicity of certain species of ''

'' 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. 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 ''

'', while the earliest isolation of anagyrine from a lupinus plant was recorded in 1939. The toxin can be found in growing leaf material in a young

lupinus ''Lupinus'', commonly known as lupin, lupine, or regionally bluebonnet, is a genus of plants in the legume family Fabaceae. The genus includes over 199 species, with centre of diversity, centres of diversity in North America, North and South A ...

plant and in the flower and seed of a mature plant, though varying concentrations of the alkaloid are present throughout lupines that contain anagyrine. It is also found in ''

Thermopsis rhombifolia ''Thermopsis rhombifolia'', also known as prairie thermopsis, is a flowering plant in the legume family. It is native to North America, where it is found in the Great Plains, with extensions into the lower canyons of the Rocky Mountains. Its na ...

'', though its role in ''T. rhombifolia'' toxicity is unknown. The first correlation between anagyrine and crooked calf disease was made by Richard Keeler in 1973.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. Recently there have been a few successful syntheses of anagyrine recorded, most notably one completed by Diane Gray and Timothy Gallagher.

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.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.Gupta, Ramesh C. Veterinary Toxicology: Basic and Clinical Principles. N.p.: Academic, 2007. Print. The IC₅₀ of anagyrine is 132 μM at

muscarinic receptors Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-recep ...

and 2,096 μM at

nicotinic receptors Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

Symptoms

Known symptoms of

crooked cow disease Crooked may refer to: * Crooked Creek (disambiguation) * Crooked Island (disambiguation) * Crooked Lake (disambiguation) * Crooked River (disambiguation) * Crooked Harbour, Hong Kong * Crooked Forest, West Pomerania, Poland * Crooked Bridge, a ra ...

include

arthrogryposis Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning 'curving of joints' (', 'joint'; ', late Latin form of late Greek ', 'hooking'). Children born with one ...

(permanently flexed joints),

torticollis Torticollis, also known as wry neck, is an extremely painful, dystonic condition defined by an abnormal, asymmetrical head or neck position, which may be due to a variety of causes. The term ''torticollis'' is derived . The most common case ha ...

(twisting of the neck),

scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...

(curving of the spine),

kyphosis Kyphosis () is an abnormally excessive convex curvature of the Spinal column, spine as it occurs in the Thoracic spine, thoracic and sacrum, sacral regions. Abnormal inward concave ''lordotic'' curving of the Cervical spine, cervical and Lumba ...

(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."AAHP Field Disease Investigation Unit (FDIU)." Crooked Calf. Washington State University: College of Veterinary Medicine, 2015. Web. 23 Apr. 2017. 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 Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that ...

, nervousness, grounding of teeth, depression, salivation,

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

, 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.Schenck, Patricia. Saunders Comprehensive Review of the Navle: Pageburst Retail. Place of Publication Not Identified: Elsevier Saunders, 2009. Print.GUPTA, RAMESH C. Reproductive and Developmental Toxicology. Place of Publication Not Identified: ELSEVIER ACADEMIC, 2017. Print.

Mechanism of Action

While the specific mechanism of action of anagyrine is unknown, the structure of anagyrine allows it to be mistaken for

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

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 Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

. Anagyrine interacts with nicotinic and

muscarinic A muscarinic acetylcholine receptor agonist, also simply known as a muscarinic agonist or as a muscarinic agent, is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, lab ...

acetylcholine receptors, however it binds to muscarinic receptors 16 times more strongly, making it likely that the blocking of

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

s is what causes crooked calf disease.

Background

Toxicity

Symptoms

Mechanism of Action

References

Further reading