Ergoline derivatives comprise a diverse group of chemical compounds whose structural skeleton is the alkaloid ergoline. Ergoline derivatives are used clinically for the purpose of vasoconstriction (5-HT1 receptor agonists—ergotamine) and in the treatment and alleviation of migraines (used with caffeine) and Parkinson's disease. Some ergoline alkaloids found in ergot fungi are implicated in the condition ergotism, which causes convulsive and gangrenous symptoms. Others are psychedelic substances, including LSD and some alkaloids in Argyreia nervosa, Ipomoea tricolor and related species.
Ergolines can pass into breast milk and should not be used during breastfeeding. They are uterine contractors that can increase the risk of miscarriage during pregnancy.
Natural occurrence
Ergoline alkaloids are found in lower fungi and some species of flowering plants: the Mexican species Turbina corymbosa and Ipomoea tricolor of the Convolvulaceae
(morning glory) family, the seeds of which were identified as the
psychedelic plant drugs known as "ololiuhqui" and "tlitliltzin",
respectively. The principal alkaloids in the seeds are ergine and its optical isomer isoergine, with several other lysergic acid derivatives and clavines present in lesser amounts. The Hawaiian species Argyreia nervosa includes similar alkaloids. It is possible, though not proven, that ergine or isoergine are responsible for the psychedelic
effects. There may be a fungal origin of the ergoline alkaloids also in
the Convolvulaceae. Like the ergot alkaloids in some monocot plants,
the ergoline alkaloids found in the plant Ipomoea asarifolia (Convolvulaceae) are produced by a seed-transmitted endophyticclavicipitaceousfungus.
History
Ergoline alkaloids were first isolated from ergot, a fungus that infects grain and causes the disease ergotism.
Ergot also has a long history of medicinal use, which led to attempts
to characterize its activity chemically. This began in 1906 with the
isolation by G. Barger and F. H. Carr of ergotoxine, so-named since it
appeared to exhibit more of the toxicity of ergot than its therapeutic
qualities. The isolation of ergotamine in 1918 by Arthur Stoll made possible the first therapeutic use of isolated ergoline alkaloids.
With the determination of the basic chemical structure of the ergot alkaloids in the early 1930s, an era of intensive exploration of synthetic derivatives began.
Ergoline derivatives
There are 3 main classes of ergoline derivatives, the water-soluble amides of lysergic acid, the water-insoluble ergopeptines (i.e., ergopeptides), and the clavine group.
Peptide ergot alkaloids or ergopeptines (also known as ergopeptides) are ergoline derivatives that contain a tripeptide structure attached to the basic ergoline ring in the same location as the amide group of the lysergic acid derivatives. This structure consists of proline and two other α-amino acids, linked in an unusual cyclol formation >N-C(OH)< with the carboxyl carbon of proline, at the juncture between the two lactam rings. Some of the important ergopeptines are summarized below. In addition to the following ergopeptines, a commonly encountered term is ergotoxine,
which refers to a mixture of equal proportions of ergocristine,
ergocornine and ergocryptine, the latter being a 2:1 mixture of alpha- and beta-ergocryptine.
Ergotoxine group (valine as the amino acid attached to the ergoline moiety, at R2 below)
Ergot (pron. /ˈɜːrɡət/UR-gət) or ergot fungi refers to a group of fungi of the genus Claviceps.
The most prominent member of this group is Claviceps purpurea ("rye ergot fungus"). This fungus grows on rye and related plants, and produces alkaloids that can cause ergotism in humans and other mammals who consume grains contaminated with its fruiting structure (called ergot sclerotium).
Claviceps includes about 50 known species, mostly in the tropical regions. Economically significant species include C. purpurea (parasitic on grasses and cereals), C. fusiformis (on pearl millet, buffel grass), C. paspali (on dallis grass), C. africana (on sorghum), and C. lutea (on paspalum). C. purpurea most commonly affects outcrossing species such as rye (its most common host), as well as triticale, wheat, and barley. It affects oats only rarely.
C. purpurea has at least three races or varieties, which differ in their host specificity:
G1 — land grasses of open meadows and fields;
G2 — grasses from moist, forest, and mountain habitats;
G3 (C. purpurea var. spartinae) — salt marsh grasses (Spartina, Distichlis).
Life cycle
An ergot kernel, called a sclerotium, develops when a spore of fungal species of the genus Claviceps infects a floret of flowering grass or cereal. The infection process mimics a pollen grain growing into an ovary during fertilization. Infection requires that the fungal spore have access to the stigma; consequently, plants infected by Claviceps are mainly outcrossing species with open flowers, such as rye (Secale cereale) and ryegrasses (genus Lolium). The proliferating fungal mycelium then destroys the plant ovary and connects with the vascular bundle originally intended for seed nutrition. The first stage of ergot infection manifests itself as a white soft tissue (known as sphacelia) producing sugary honeydew, which often drops out of the infected grass florets. This honeydew contains millions of asexual spores (conidia), which insects
disperse to other florets. Later, the sphacelia convert into a hard dry
sclerotium inside the husk of the floret. At this stage, alkaloids and lipids accumulate in the sclerotium.
Claviceps species from tropic and subtropic regions produce macro- and microconidia in their honeydew.
Macroconidia differ in shape and size between the species, whereas
microconidia are rather uniform, oval to globose (5x3μm). Macroconidia
are able to produce secondary conidia. A germ tube emerges from a
macroconidium through the surface of a honeydew drop and a secondary
conidium of an oval to pearlike shape is formed, to which the contents
of the original macroconidium migrates. Secondary conidia form a white,
frost-like surface on honeydew drops and spread via the wind. No such
process occurs in Claviceps purpurea, Claviceps grohii, Claviceps nigricans, and Claviceps zizaniae, all from northern temperate regions.
When a mature sclerotium drops to the ground, the fungus remains
dormant until proper conditions (such as the onset of spring or a rain
period) trigger its fruiting phase. It germinates, forming one or
several fruiting bodies with heads and stipes, variously coloured (resembling a tiny mushroom). In the head, threadlike sexual
spores form, which are ejected simultaneously when suitable grass hosts
are flowering. Ergot infection causes a reduction in the yield and
quality of grain and hay, and if livestock eat infected grain or hay it
may cause a disease called ergotism.
Black and protruding sclerotia of C. purpurea are well
known. However, many tropical ergots have brown or greyish sclerotia,
mimicking the shape of the host seed. For this reason, the infection is
often overlooked.
Insects, including flies and moths, carry conidia of Claviceps species, but it is unknown whether insects play a role in spreading the fungus from infected to healthy plants.
Evolution
The evolution of plant parasitism in the Clavicipitaceae dates back at least 100 million years, to the early-mid Cretaceous. An amber fossil discovered in 2014 preserves a grass spikelet
and an ergot-like parasitic fungus. The fossil shows that the original
hosts of the Clavicipitaceae could have been grasses. The discovery also
establishes a minimum time for the conceivable presence of psychotropic compounds in fungi.
Several evolutionary processes have acted to diversify the array of
ergot alkaloids produced by fungi; these differences in enzyme
activities are evident at the levels of substrate specificity (LpsA),
product specification (EasA, CloA) or both (EasG and possibly CloA).
The “old yellow enzyme,” EasA, presents an outstanding example. This
enzyme catalyzes reduction of the C8=C9 double-bond in chanoclavine I,
but EasA isoforms differ in whether they subsequently catalyze
reoxidation of C8–C9 after rotation.
This difference distinguishes most Clavicipitaceae from Trichocomaceae,
but in Clavicipitaceae it is also the key difference dividing the
branch of classical ergot alkaloids from dihydroergot alkaloids, the
latter often being preferred for pharmaceuticals due to their relatively
few side effects.
Effects on humans and other mammals
Ergot-derived drug to stop postpartum bleeding
The ergot sclerotium contains high concentrations (up to 2% of dry mass) of the alkaloidergotamine, a complex molecule consisting of a tripeptide-derived cyclol-lactam ring connected via amide linkage to a lysergic acid (ergoline) moiety, and other alkaloids of the ergoline group that are biosynthesized by the fungus. Ergot alkaloids have a wide range of biological activities including effects on circulation and neurotransmission.
Ergot alkaloids are classified as:
derivatives of 6,8-dimethylergoline and
lysergic acid derivatives.
Ergotism
is the name for sometimes severe pathological syndromes affecting
humans or other animals that have ingested plant material containing
ergot alkaloid, such as ergot-contaminated grains. The Hospital Brothers of St. Anthony, an order of monks established in 1095, specialized in treating ergotism victims
with balms containing tranquilizing and circulation-stimulating plant
extracts. The common name for ergotism is "St. Anthony's Fire", in reference to this order of monks and the severe burning sensations in the limbs which was one of the symptoms.
There are two types of ergotism, the first is characterized by muscle
spasms, fever and hallucinations and the victims may appear dazed, be
unable to speak, become manic, or have other forms of paralysis or
tremors, and suffer from hallucinations and other distorted perceptions. This is caused by serotonergic stimulation of the central nervous system by some of the alkaloids.
The second type of ergotism is marked by violent burning, absent
peripheral pulses and shooting pain of the poorly vascularized distal
organs, such as the fingers and toes, and are caused by effects of ergot alkaloids on the vascular system due to vasoconstriction, sometimes leading to gangrene and loss of limbs due to severely restricted blood circulation.
The neurotropic activities of the ergot alkaloids may also cause hallucinations and attendant irrational behaviour, convulsions, and even death. Other symptoms include strong uterine contractions, nausea, seizures,
high fever, vomiting, loss of muscle strength and unconsciousness.
Since the Middle Ages, controlled doses of ergot were used to induce abortions and to stop maternal bleeding after childbirth.[17]
Klotz offers a detailed overview of the toxicities in mammalian
livestock, stating that the activities are attributable to antagonism or
agonism of neurotransmitters, including dopamine, serotonin and norepinephrine. As well, he shares that the adrenergic blockage by ergopeptines (e.g., ergovaline or ergotamine) leads to potent and long-term vasoconstriction, and can result in reduced blood flow resulting in intense burning pain (St. Anthony’s fire), edema, cyanosis, dry gangrene and even loss of hooves in cattle or limbs in humans. Reduced prolactin
due to ergot alkaloid activity on dopamine receptors in the pituitary
is also common in livestock. Reduced serum prolactin is associated with
various reproductive problems in cattle, and especially in horses,
including agalactia and poor conception, and late-term losses of foals and sometimes mares due to dystocia and thickened placentas.
Although both gangrenous and convulsive symptoms are seen in naturally
occurring ergotism resulting from the ingestion of fungus infected rye,
only gangrenous ergotism has been reported following the excessive
ingestion of ergotamine tartrate.
Ergot extract has been used in pharmaceutical preparations, including ergot alkaloids in products such as Cafergot (containing caffeine and ergotamine or ergoline) to treat migraine headaches, and ergometrine, used to induce uterine contractions and to control bleeding after childbirth.
Clinical ergotism as seen today results almost exclusively from the
excessive intake of ergotamine tartrate in the treatment of migraine
headache.
In addition to ergot alkaloids, Claviceps paspali also produces tremorgens (paspalitrem) causing "paspalum staggers" in cattle. The fungi of the genera Penicillium and Aspergillus also produce ergot alkaloids, notably some isolates of the human pathogen Aspergillus fumigatus, and have been isolated from plants in the family Convolvulaceae, of which morning glory
is best known. The causative agents of most ergot poisonings are the
ergot alkaloid class of fungal metabolites, though some ergot fungi
produce distantly related indole-diterpene alkaloids that are
tremorgenic.
Ergot does not contain lysergic acid diethylamide (LSD) but instead contains lysergic acid as well as its precursor, ergotamine.
Lysergic acid is a precursor for the synthesis of LSD. Their realized
and hypothesized medicinal uses have encouraged intensive research since
the 1950s culminating on the one hand in development of drugs both
legal (e.g., bromocriptine)
and illegal (e.g., lysergic acid diethylamide= LSD), and on the other
hand in extensive knowledge of the enzymes, genetics, and diversity of
ergot alkaloid biosynthetic pathways.
The January 4, 2007 issue of the New England Journal of Medicine includes a paper that documents a British study of more than 11,000 Parkinson's disease patients. The study found that two ergot-derived drugs, pergolide and cabergoline, commonly used to treat Parkinson's Disease may increase the risk of leaky heart valves by up to 700%.
History
Ergot on wheat stalks
Ergotism is the earliest recorded example of mycotoxicosis, or poisoning caused by toxic molds.
Early references to ergot poisoning (ergotism) date back as far as 600 BC, an Assyrian tablet referred to it as a 'noxious pustule in the ear of grain'. In 350 BC, the Parsees described 'noxious grasses that cause pregnant women to drop the womb and die in childbed'. In ancient Syria, ergot was called 'Daughter of Blood'. Radulf Glaber described an ailment he called 'hidden fire' or ignus ocultus, in which a burning of the limb is followed by its separation from the body, often consuming the victim in one night. In 1588, Johannes Thallius wrote that it is called 'Mother of Rye', or rockenmutter, and is used to halt bleeding.
Human poisoning due to the consumption of rye bread made from ergot-infected grain was common in Europe in the Middle Ages. The first mention of a plague of gangrenous ergotism in Europe comes from Germany in 857, following this France and Scandinavia experienced similar outbreaks;
England is noticeably absent from the historical regions affected by
ergotism as their main source of food was wheat, which is resistant to
ergot fungi. In 944, a massive outbreak of ergotism caused 40,000 deaths in the regions of Aquitaine, Limousin, Perigord, and Angoumois in France. In Hesse in 1596, Wendelin Thelius was one of the first to attribute ergotism poisoning to grain. In 1778, S. Tessier, observing a huge epidemic in Sologne,
France in which more than 8,000 people died, recommended drainage of
fields, compulsory cleaning of grain, and the substitution of potatoes
for affected grain.
Saint Anthony's fire and the Antonites
In 1722, the Russian Tzar Peter the Great was thwarted in his campaign against the Ottoman Empire
as his army, traveling down the Terek steppe, were struck by ergotism
and were forced to retreat in order to find edible grains. A diary entry
from the time describes that as soon as people ate the poisoned bread
they became dizzy, with such strong nerve contractions that those who
did not die from the first day found their hands and feet falling off,
akin to frostbite. The epidemic was known as Saint Anthony's fire, or ignis sacer, and some historical events, such as the Great Fear in France during the French Revolution have been linked to ergot poisoning. Saint Anthony was a 3rd Century Egyptian ascetic who lived by the Red Sea and was known for long fasting in which he confronted terrible visions and temptations sent from the Devil. He was credited by two noblemen for assisting them in recovery from the disease; they subsequently founded the Order of St. Anthony in honor of him. Anthony was a popular subject for art in the Middle Ages and his symbol is a large blue "T" sewn onto the shoulder of the order's monks, symbolizing the crutch used by the ill and injured.
The Order of St. Anthony, who were also known as Antonites, grew
quickly and hospitals spread through France, Germany, and Scandinavia
and gained wealth and power as grateful patrons bestowed money and
charitable goods to the hospitals. By the end of the Middle Ages, there were 396 settlements and 372 hospitals owned by the order
and pilgrimages to such hospitals became popular as well as the
donation of limbs lost to ergotism, which were displayed near shrines to
the saint. These hagiotherapeutic
centers were the first specialized European medical welfare systems and
the friars of the order were knowledgeable about treatment of ergotism
and the horrifying effects of the poison. The sufferers would receive ergot-free meals, wines containing vasodilating and analgesic herbs, and applications of Antonites-balsalm, which was the first transdermal therapeutic system (TTS) in medical history. Their medical recipes have been lost to time, though some recorded treatments still remain.
After 1130 AD, the monks were no longer permitted to perform
operations, and so barber surgeons were employed to remove gangrenous
limbs and treat open sores. Three barbers founded a hospital in Memmingen
in 1214 and accepted those who were afflicted with the gangrenous form
of ergotism. Patients were fed and housed with the more able-bodied
individuals acting as orderlies and assistants. Patients with the
convulsive form of ergotism, or ergotismus convulsivus, were
welcomed for only nine days before they were asked to leave as
convulsive ergotism was seen as less detrimental. Though the sufferers
often experienced irreversible effects, they most often returned to
their families and resumed their livelihoods.
An important aspect to the Order of St. Anthony's treatment
practices was the exclusion of rye bread and other ergot-containing
edibles, which halted the progression of ergotism.
There was no known cure for ergotism itself, however there was
treatment of the symptoms, which often included blood constriction,
nervous disorder, and/or hallucinations; if the sufferer survived the
initial poisoning, his limbs would often fall off and he or she would
continue to improve in health if they halted consumption of ergot.
The trunk of the body remained relatively untouched by the disease
until its final stages and the victims, not understanding the cause of
their ailment, would continue to imbibe ergot-laden food for weeks until
the condition reached their digestive system.
It is believed that the peasantry and children were most susceptible to
ergotism, though the wealthy were afflicted as well, as at times entire
villages relied on tainted crops for sustenance and during times of
famine, ergotism reached into every house.
Ergot fungus is impervious to heat and water, thus it was most often
baked into bread through rye flour; though other grasses can be
infected, it was uncommon in Medieval Europe to consume grasses other than rye.
The physiological effects of ergot depended upon the concentration and
combinations of the ingested ergot metabolites, as well as the age and
nutritional status of the afflicted individual. The Antonites began to decline after physicians discovered the genesis of ergotism and recommended methods for removing the sclerotium from the rye crops. In 1776, the cloisters of the Antonites were incorporated into the Maltese Knights Hospitaller,
losing much of their medical histories in the process and losing the
ergotism cures and recipes due to lack of use and lack of preservation.
Usage in gynaecology and obstetrics
Midwives and very few doctors in Europe have used extracts from ergot for centuries:
In a Nürnberg manuscript of 1474 powdered ergot was prescribed together with Laurel-fruits and rhizomes of Salomon’s seals to cure »permutter« or »heffmutter«, that means pain in the lower abdomen caused by the »uprising of the womb«
In a printed book of 1582 the German physician Adam Lonicer
wrote, that three sclerotia of ergot, used several times a day, were
used by midwives as a good remedy in case of the »uprising and pain of
the womb« (»auffſteigen vnd wehethumb der mutter«)
To prove, that ergot is a harmless sort of grain, in 1774 the French pharmacist Antoine-Augustin Parmentier edited a letter, he had received from Madame Dupile, a midwife of Chaumont-en-Vexin. She had told him, that if uterine contractions were too weak in the expulsion stage of childbirth she and her mother gave peeled ergot in an amount of the filling of a thimble solved in water, wine or broth. The administration of ergot was followed by a mild childbirth within 15 minutes. The French physician Jean-Baptiste Desgranges (1751–1831) published in 1818, that in 1777 he had met midwives in Lyon,
who successfully treated feeble uterine contractions by administering
the powder of ergot. Desgranges joined this remedy into his therapeutic
arsenal. From 1777 to 1804 he was successful in alleviating childbirth
for more than twenty women by the administration of the powder of
ergot. He never saw any side-effect of this treatment.
In 1807 Dr. John Stearns of Saratoga County wrote to a friend, that he had used over several years a »pulvis parturiens« with complete success in patients with »lingering parturitation«. This »pulvis parturiens« consisted of ergot, that he called a »spurious groth of rye«. He boiled »half a drachm« (ca. 2g) of that powder in half a pint of water and gave one third every twenty minutes, till the pains commenced. In 1813 Dr. Oliver Prescott (1762–1827) of Newburyport
published a dissertation "on the natural history and medical effects of
the secale cornutum,” in which he described and analysed the experience
he had gathered over five years while using ergot in cases of poor
uterine action in the second stage of labour in childbirth.
The 1836 Dispensatory of the United States recommended »to
a woman in labour fifteen or twenty grains [ca. 1 to 1,3g] of ergot in
powder to be repeated every twenty minutes, till its peculiar effects
are experienced, or till the amount of a drachm [ca. 3,9g] has been
taken«.
In 1837 the French Codex Pharmacopee Francaise required ergot to be kept in all pharmacies.
Low to very low evidence from clinical trials suggests that
prophylactic use of ergot alkaloids, administered by intravenous (IV) or
intramuscular (IM) in the third stage of labor, may reduce blood loss
and may reduce the risk of moderate to severe hemorrhage following
delivery, however this medication may also be associated with higher
blood pressure and higher pain. It is not clear of oral ergo alkaloids are beneficial or harmful as they have not been well studied.
A 2018 Cochrane Systematic Review concluded that other medications such
as oxytocin, syntometrine and prostaglandins, may be preferred over
ergot alkaloids.
Though ergot was known to cause abortions in cattle
and humans, it was not a recognized use for it as abortion was illegal
in most countries, thus evidence for its use in abortion is unknown.
Most often, ergot was used to speed the process of parturition or
delivery, and was not used for the purpose of halting postpartum
bleeding, which is a concern of childbirth. However, until anesthesia
became available, there was no antidote or way of controlling the
effects of ergot. So if the fetus did not move as expected, the drug
could cause the uterus to mold itself around the child, rupturing the
uterus and killing the child. David Hosack, an American physician, noted the large number of stillbirths resulting from ergot use and stated that rather than pulvis ad partum, it should be called pulvis ad mortem.
He began advocating for its use to halt postpartum bleeding.
Eventually, doctors determined that the use of ergot in childbirth
without an antidote was too dangerous. They ultimately restricted its
use to expelling the placenta
or stopping hemorrhage. Not only did it constrict the uterus, ergot had
the ability to increase or decrease blood pressure, induce hypothermia
and emesis, and influence pituitary hormone secretions.
In 1926, Swiss psychiatrist Hans Maier suggested to use ergotamine for
the treatment of vascular headaches of the migraine type.
In the 1930s, abortifacient
drugs were marketed to women by various companies under various names
such as Molex pills and Cote pills. Since birth control devices and
abortifacients were illegal to market and sell at the time, they were
offered to women who were "delayed". The recommended dosage was seven
grains of ergotin a day. According to the United StatesFederal Trade Commission (FTC) these pills contained ergotin, aloes, Black Hellebore,
and other substances. The efficacy and safety of these pills are
unknown. The FTC deemed them unsafe and ineffective and demanded that
they cease and desist selling the product. Currently, over a thousand
compounds have been derived from ergot ingredients.
British author John Grigsby contends that the presence of ergot in the stomachs of some of the so-called 'bog-bodies' (Iron Age human remains from peat bogs Northeast Europe, such as the Tollund Man) is indicative of use of Claviceps purpurea in ritual drinks in a prehistoric fertility cult akin to the Greek Eleusinian Mysteries. In his 2005 book Beowulf and Grendel, he argues that the Anglo-Saxon poem Beowulf is based on a memory of the quelling of this fertility cult by followers of Odin. He writes that Beowulf, which he translates as barley-wolf, suggests a connection to ergot which in German was known as the 'tooth of the wolf'.
Linnda R. Caporael posited in 1976 that the hysterical symptoms of young women that had spurred the Salem witch trials had been the result of consuming ergot-tainted rye.
However, Nicholas P. Spanos and Jack Gottlieb, after a review of the
historical and medical evidence, later disputed her conclusions. Other authors have likewise cast doubt on ergotism as the cause of the Salem witch trials.
Claviceps purpurea
Mankind has known about Claviceps purpurea for a long time, and its appearance has been linked to extremely cold winters that were followed by rainy summers.
The sclerotial stage of C. purpurea conspicuous on the
heads of ryes and other such grains is known as ergot. Favorable
temperatures for growth are in the range of 18–30 °C. Temperatures above
37 °C cause rapid germination of conidia. Sunlight has a chromogenic effect on the mycelium, with intense coloration. Cereal mashes and sprouted rye are suitable substrates for growth of the fungus in the laboratory.
Claviceps africana
Claviceps africana infects sorghum.
In sorghum and pearl millet, ergot became a problem when growers
adopted hybrid technology, which increased host susceptibility. It only infects unfertilized ovaries, so self-pollination and fertilization can decrease the presence of the disease, but male-sterile lines are extremely vulnerable to infection. Symptoms of infection by C. africana include the secretion of honeydew (a fluid with high concentrates of sugar and conidia), which attracts insects like flies, beetles, and wasps that feed on it. This helps spread the fungus to uninfected plants.
C. africana caused ergot disease that caused a famine in 1903-1906 in Northern Cameroon, West Africa, and also occurs in eastern and southern Africa, especially Zimbabwe and South Africa.
Male sterile sorghums (also referred to as A-lines) are especially
susceptible to infection, as first recognized in the 1960s, and massive
losses in seed yield have been noted. Infection is associated with cold
night temperatures that are below 12 °C occurring two to three weeks
before flowering.
Sorghum ergot caused by Claviceps africana Frederickson,
Mantle and De Milliano is widespread in all sorghum growing areas,
whereas the species was formerly restricted to Africa and Asia where it
was first recorded more than 90 years ago, it has been spreading rapidly
and by the mid-1990s it reached Brazil, South Africa, and Australia. By 1997, the disease had spread to most South American countries and the Caribbean including Mexico, and by 1997 had reached Texas in the United States.
The boundary between alkaloids and other nitrogen-containing natural compounds is not clear-cut. Compounds like amino acidpeptides, proteins, nucleotides, nucleic acid, amines, and antibiotics are usually not called alkaloids. Natural compounds containing nitrogen in the exocyclic position (mescaline, serotonin, dopamine, etc.) are usually classified as amines rather than as alkaloids. Some authors, however, consider alkaloids a special case of amines.
Naming
The article that introduced the concept of "alkaloid".
The name "alkaloids" (German: Alkaloide) was introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meißner, and is derived from late Latin root alkali (which, in turn, comes from the Arabic al-qalwī meaning 'ashes of plants') and the suffix -οειδής -('like').
However, the term came into wide use only after the publication of a
review article, by Oscar Jacobsen in the chemical dictionary of Albert Ladenburg in the 1880s.
There is no unique method for naming alkaloids. Many individual names are formed by adding the suffix "ine" to the species or genus name. For example, atropine is isolated from the plant Atropa belladonna; strychnine is obtained from the seed of the Strychnine tree (Strychnos nux-vomica L.).
Where several alkaloids are extracted from one plant their names are
often distinguished by variations in the suffix: "idine", "anine",
"aline", "inine" etc. There are also at least 86 alkaloids whose names
contain the root "vin" because they are extracted from vinca plants such as Vinca rosea (Catharanthus roseus); these are called vinca alkaloids.
History
Friedrich Sertürner, the German chemist who first isolated morphine from opium.
Alkaloid-containing plants have been used by humans since ancient
times for therapeutic and recreational purposes. For example, medicinal
plants have been known in Mesopotamia from about 2000 BC. The Odyssey
of Homer referred to a gift given to Helen by the Egyptian queen, a
drug bringing oblivion. It is believed that the gift was an
opium-containing drug. A Chinese book on houseplants written in 1st–3rd centuries BC mentioned a medical use of ephedra and opium poppies. Also, coca leaves have been used by South American Indians since ancient times.
Extracts from plants containing toxic alkaloids, such as aconitine and tubocurarine, were used since antiquity for poisoning arrows.
Studies of alkaloids began in the 19th century. In 1804, the German chemist Friedrich Sertürner isolated from opium a "soporific principle" (Latin: principium somniferum), which he called "morphium", referring to Morpheus,
the Greek god of dreams; in German and some other Central-European
languages, this is still the name of the drug. The term "morphine", used
in English and French, was given by the French physicist Joseph Louis Gay-Lussac.
A significant contribution to the chemistry of alkaloids in the
early years of its development was made by the French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou, who discovered quinine (1820) and strychnine (1818). Several other alkaloids were discovered around that time, including xanthine (1817), atropine (1819), caffeine (1820), coniine (1827), nicotine (1828), colchicine (1833), sparteine (1851), and cocaine (1860). The development of the chemistry of alkaloids was accelerated by the emergence of spectroscopic and chromatographic methods in the 20th century, so that by 2008 more than 12,000 alkaloids had been identified.
The first complete synthesis of an alkaloid was achieved in 1886 by the German chemist Albert Ladenburg. He produced coniine by reacting 2-methylpyridine with acetaldehyde and reducing the resulting 2-propenyl pyridine with sodium.
Bufotenin, an alkaloid from some toads, contains an indole core, and is produced in living organisms from the amino acid tryptophan.
Compared with most other classes of natural compounds, alkaloids are
characterized by a great structural diversity. There is no uniform
classification.
Initially, when knowledge of chemical structures was lacking, botanical
classification of the source plants was relied on. This classification
is now considered obsolete.
More recent classifications are based on similarity of the carbon skeleton (e.g., indole-, isoquinoline-, and pyridine-like) or biochemical precursor (ornithine, lysine, tyrosine, tryptophan, etc.). However, they require compromises in borderline cases; for example, nicotine contains a pyridine fragment from nicotinamide and a pyrrolidine part from ornithine and therefore can be assigned to both classes.
Alkaloids are often divided into the following major groups:
"True alkaloids" contain nitrogen in the heterocycle and originate from amino acids. Their characteristic examples are atropine, nicotine, and morphine. This group also includes some alkaloids that besides the nitrogen heterocycle contain terpene (e.g., evonine) or peptide fragments (e.g.ergotamine). The piperidine alkaloids coniine and coniceine may be regarded as true alkaloids (rather than pseudoalkaloids: see below) although they do not originate from amino acids.
"Protoalkaloids", which contain nitrogen (but not the nitrogen heterocycle) and also originate from amino acids. Examples include mescaline, adrenaline and ephedrine.
Pseudoalkaloids – alkaloid-like compounds that do not originate from amino acids. This group includes terpene-like and steroid-like alkaloids, as well as purine-like alkaloids such as caffeine, theobromine, theacrine and theophylline. Some authors classify as pseudoalkaloids such compounds such as ephedrine and cathinone. Those originate from the amino acid phenylalanine, but acquire their nitrogen atom not from the amino acid but through transamination.
Some alkaloids do not have the carbon skeleton characteristic of their group. So, galanthamine and homoaporphines do not contain isoquinoline fragment, but are, in general, attributed to isoquinoline alkaloids.
Properties
Head of a calf born to a cow that ate leaves of the corn lily plant. The cyclopia in the calf is induced by the alkaloid cyclopamine present in the plant.
Most alkaloids contain oxygen in their molecular structure; those
compounds are usually colorless crystals at ambient conditions.
Oxygen-free alkaloids, such as nicotine or coniine, are typically volatile, colorless, oily liquids. Some alkaloids are colored, like berberine (yellow) and sanguinarine (orange).
Most alkaloids are weak bases, but some, such as theobromine and theophylline, are amphoteric. Many alkaloids dissolve poorly in water but readily dissolve in organic solvents, such as diethyl ether, chloroform or 1,2-dichloroethane. Caffeine, cocaine, codeine and nicotine are slightly soluble in water (with a solubility of ≥1g/L), whereas others, including morphine and yohimbine
are very slightly water-soluble (0.1–1 g/L). Alkaloids and acids form
salts of various strengths. These salts are usually freely soluble in
water and ethanol and poorly soluble in most organic solvents. Exceptions include scopolamine hydrobromide, which is soluble in organic solvents, and the water-soluble quinine sulfate.
Most alkaloids have a bitter taste or are poisonous when
ingested. Alkaloid production in plants appeared to have evolved in
response to feeding by herbivorous animals; however, some animals have
evolved the ability to detoxify alkaloids.
Some alkaloids can produce developmental defects in the offspring of
animals that consume but cannot detoxify the alkaloids. One example is
the alkaloid cyclopamine, produced in the leaves of corn lily.
During the 1950s, up to 25% of lambs born by sheep that had grazed on
corn lily had serious facial deformations. These ranged from deformed
jaws to cyclopia
(see picture). After decades of research, in the 1980s, the compound
responsible for these deformities was identified as the alkaloid
11-deoxyjervine, later renamed to cyclopamine.
Alkaloids are generated by various living organisms, especially by higher plants – about 10 to 25% of those contain alkaloids. Therefore, in the past the term "alkaloid" was associated with plants.
The alkaloids content in plants is usually within a few percent
and is inhomogeneous over the plant tissues. Depending on the type of
plants, the maximum concentration is observed in the leaves (black henbane), fruits or seeds (Strychnine tree), root (Rauvolfia serpentina) or bark (cinchona). Furthermore, different tissues of the same plants may contain different alkaloids.
Beside plants, alkaloids are found in certain types of fungi, such as psilocybin in the fungus of the genus Psilocybe, and in animals, such as bufotenin in the skin of some toads and a number of insects, markedly ants. Many marine organisms also contain alkaloids. Some amines, such as adrenaline and serotonin,
which play an important role in higher animals, are similar to
alkaloids in their structure and biosynthesis and are sometimes called
alkaloids.
Because of the structural diversity of alkaloids, there is no single method of their extraction from natural raw materials. Most methods exploit the property of most alkaloids to be soluble in organic solvents but not in water, and the opposite tendency of their salts.
Most plants contain several alkaloids. Their mixture is extracted first and then individual alkaloids are separated. Plants are thoroughly ground before extraction. Most alkaloids are present in the raw plants in the form of salts of organic acids. The extracted alkaloids may remain salts or change into bases.
Base extraction is achieved by processing the raw material with
alkaline solutions and extracting the alkaloid bases with organic
solvents, such as 1,2-dichloroethane, chloroform, diethyl ether or
benzene. Then, the impurities are dissolved by weak acids; this converts
alkaloid bases into salts that are washed away with water. If
necessary, an aqueous solution of alkaloid salts is again made alkaline
and treated with an organic solvent. The process is repeated until the
desired purity is achieved.
In the acidic extraction, the raw plant material is processed by a weak acidic solution (e.g., acetic acid
in water, ethanol, or methanol). A base is then added to convert
alkaloids to basic forms that are extracted with organic solvent (if the
extraction was performed with alcohol, it is removed first, and the
remainder is dissolved in water). The solution is purified as described
above.
Alkaloids are separated from their mixture using their different
solubility in certain solvents and different reactivity with certain
reagents or by distillation.
A number of alkaloids are identified from insects, among which the fire antvenom alkaloids known as solenopsins have received greater attention from researchers. These insect alkaloids can be efficiently extracted by solvent immersion of live fire ants or by centrifugation of live ants followed by silica-gel chromatography purification.
Tracking and dosing the extracted solenopsin ant alkaloids has been
described as possible based on their absorbance peak around 232
nanometers.
Schiff bases can be obtained by reacting amines with ketones or aldehydes. These reactions are a common method of producing C=N bonds.
In the biosynthesis of alkaloids, such reactions may take place within a molecule, such as in the synthesis of piperidine:
Mannich reaction
An integral component of the Mannich reaction, in addition to an amine and a carbonyl compound, is a carbanion, which plays the role of the nucleophile in the nucleophilic addition to the ion formed by the reaction of the amine and the carbonyl.
The Mannich reaction can proceed both intermolecularly and intramolecularly:
Dimer alkaloids
In addition to the described above monomeric alkaloids, there are also dimeric, and even trimeric and tetrameric
alkaloids formed upon condensation of two, three, and four monomeric
alkaloids. Dimeric alkaloids are usually formed from monomers of the
same type through the following mechanisms:
There are also dimeric alkaloids formed from two distinct monomers, such as the vinca alkaloids vinblastine and vincristine, which are formed from the coupling of catharanthine and vindoline. The newer semi-synthetic chemotherapeutic agent vinorelbine is used in the treatment of non-small-cell lung cancer. It is another derivative dimer of vindoline and catharanthine and is synthesised from anhydrovinblastine, starting either from leurosine or the monomers themselves.
Biological role
The role of alkaloids for living organisms that produce them is still unclear. It was initially assumed that the alkaloids are the final products of nitrogenmetabolism in plants, as urea in mammals. It was later shown that alkaloid concentration varies over time, and this hypothesis was refuted. A number of ants are suggested to also produce alkaloids as venom components, however the exact biosynthesis pathways have not been empirically demonstrated.
Most of the known functions of alkaloids are related to protection. For example, aporphine alkaloid liriodenine produced by the tulip tree protects it from parasitic mushrooms. In addition, the presence of alkaloids in the plant prevents insects and chordate animals from eating it. However, some animals are adapted to alkaloids and even use them in their own metabolism. Such alkaloid-related substances as serotonin, dopamine and histamine are important neurotransmitters in animals. Alkaloids are also known to regulate plant growth. One example of an organism that uses alkaloids for protection is the Utetheisa ornatrix,
more commonly known as the ornate moth. Pyrrolizidine alkaloids render
these larvae and adult moths unpalatable to many of their natural
enemies like coccinelid beetles, green lacewings, insectivorous
hemiptera and insectivorous bats. Another example of alkaloids being utilized occurs in the poison hemlock moth (Agonopterix alstroemeriana). This moth feeds on its highly toxic and alkaloid-rich host plant poison hemlock (Conium maculatum) during its larval stage. A. asltroemeriana
may benefit twofold from the toxicity of the naturally-occurring
alkaloids, both through the unpalatability of the species to predators
and through the ability of A. alstroemeriana to recognize Conium maculatum as the correct location for oviposition. A fire antvenom alkaloid known as solenopsin has been demonstrated to protect queens of invasive fire ants during the foundation of new nests, thus playing a central role in the spread of this pest ant species around the world.
Applications
In medicine
Medical
use of alkaloid-containing plants has a long history, and, thus, when
the first alkaloids were isolated in the 19th century, they immediately
found application in clinical practice. Many alkaloids are still used in medicine, usually in the form of salts widely used including the following:
Many synthetic and semisynthetic drugs are structural modifications
of the alkaloids, which were designed to enhance or change the primary
effect of the drug and reduce unwanted side-effects. For example, naloxone, an opioid receptorantagonist, is a derivative of thebaine that is present in opium.
Prior to the development of a wide range of relatively low-toxic synthetic pesticides, some alkaloids, such as salts of nicotine and anabasine, were used as insecticides. Their use was limited by their high toxicity to humans.
