Ergot
Medicinal ergot is the dried sclerotium of the fungus
Claviceps purpurea (Clavicipitaceae)
developed on the ovary of rye,
Secale cereale (Graminae/Poaceae). Ergot is a fungal disease of
wild and cultivated grasses, and initially affects the flowers. In due course, a dark sclerotium,
the resting stage of the fungus, is developed instead of the normal seed. This protrudes
from the seed head, the name ergot being derived from the French word argot - a spur. The
sclerotia fall to the ground, germinating in the spring and reinfecting grasses or grain crops
by means of spores. Two types of spore are recognized: ascospores, which are formed in
the early stages and are dispersed by the wind, whilst later on conidiospores are produced,
which are insect distributed. The flowers are only susceptible to infection before pollination.
Ergots may subsequently be harvested with the grain and contaminate flour or animal feed.
The consumption of ergot-infected rye has resulted in the disease ergotism, which has a long,
well documented history.
There are three broad clinical features of ergot poisoning, which are due to the alkaloids
present and the relative proportions of each component:
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Alimentary upsets, e.g. diarrhoea, abdominal pains, and vomiting. |
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Circulatory changes, e.g. coldness of hands and feet due to a vasoconstrictor effect, a
decrease in the diameter of blood vessels, especially those supplying the extremeties. |
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Neurological symptoms, e.g. headache, vertigo, convulsions, psychotic disturbances, and
hallucinations. |
These effects usually disappear on removal of the source of poisoning, but much more serious
problems develop with continued ingestion, or with heavy doses of ergot-contaminated food.
The vasoconstrictor effect leads to restricted blood flow in small terminal arteries, death of
the tissue, the development of gangrene, and even the shedding of hands, feet, or limbs.
Gangrenous ergotism was known as St Anthony's Fire, the Order of St Anthony traditionally
caring for sufferers in the Middle Ages. The neurological effects were usually manifested by
severe and painful convulsions. Outbreaks of the disease in both humans and animals were
relatively frequent in Europe in the Middle Ages, but once the cause had been established
it became relatively simple to avoid contamination. Separation of the ergots from grain, or
the use of fungicides during cultivation of the crop, have removed most of the risks, though
infection of crops is still common.
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| Figure 103 |
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| Table 6.1 |
The ergot sclerotia contain from 0.15-0.5% alkaloids, and more than 50 have been
characterized. The medicinally useful compounds are derivatives of (+)-lysergic acid
(Figure 103), and can be separated into two groups, the water-soluble amino alcohol
derivatives (up to about 20% of the total alkaloids), and water-insoluble peptide derivatives
(up to 80% of the total alkaloids). Ergometrine (Figure 103) (also known as ergonovine in
the USA and ergobasine in Switzerland) is an amide of lysergic acid and 2-aminopropanol,
and is the only significant member of the first group. The peptide derivatives contain a cyclized tripeptide fragment bonded to lysergic acid via an amide linkage. Based on the
nature of the three amino acids, these structures can be subdivided into three groups, the
ergotamine group, the ergoxine group, and the ergotoxine group (Table 6.1). The amino acids
involved are alanine, valine, leucine, isoleucine, phenylalanine, proline, and α-aminobutyric
acid, in various combinations (Figure 104). All contain proline in the tripeptide, and
one of the amino acids is effectively incorporated into the final structure in the form of an
a-hydroxy-a-amino acid. Thus, ergotamine incorporates alanine, phenylalanine, and proline
residues in its peptide portion. Hydrolysis gives (+)&minuslysergic acid, proline, and phenylalanine, together with pyruvic acid and ammonia, the latter hydrolysis products a consequence of the
additional hydroxylation involving alanine (Figure 104). Hydrolysis of the ergotoxine group
of alkaloids results in the proximal valine unit being liberated as dimethylpyruvic acid (not
systematic nomenclature) and ammonia, and the ergoxine group similarly yields α-oxobutyric
acid from the α-aminobutyric acid fragment. The alkaloid 'ergotoxine' was originally thought
to be a single compound, but was subsequently shown to be a mixture of alkaloids. The
proposed structures β-ergosine and β-ergoptine, which complete the combinations shown in
Table 6.1, have not yet been isolated as natural products.
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| Figure 104 |
Medicinal ergot is cultivated in the Czech Republic, Germany, Hungary, Switzerland,
Austria, and Poland. Fields of rye are infected artificially with spore cultures of Claviceps
purpurea, either by spraying or by a mechanical process that uses needles dipped in a spore
suspension. The ergots are harvested by hand, by machine, or by separation from the ripe
grain by flotation in a brine solution. By varying the strain of the fungal cultures, it is possible
to maximize alkaloid production (0.4-1.2%), or give alkaloid mixtures in which particular
components predominate. Ergots containing principally ergotamine in concentrations of
about 0.35% can be cultivated. In recent times, ergot of wheat (
Triticum aestivum), and the
wheat-rye hybrid triticale (
Triticosecale) have been produced commercially.
Alternatively, the ergot alkaloids can be produced by culturing the fungus. Initially, cultures
of the rye parasite
Claviceps purpurea in fermentors did not give the typical alkaloids
associated with the sclerotia, e.g. ergometrine and ergotamine. These medicinally useful
compounds appear to be produced only in the later stages of development of the fungus.
Instead, the cultures produced alkaloids that were not based on lysergic acid, and are
now recognized as intermediates in the biosynthesis of lysergic acid, e.g. chanoclavine-
I, agroclavine, and elymoclavine (Figure 101). Ergot alkaloids that do not yield lysergic
acid on hydrolysis have been termed clavine alkaloids. Useful derivatives based on lysergic
acid can be obtained by fermentation growth of another fungal species, namely
Claviceps
paspali. Although some strains are available that produce peptide alkaloids in culture, other
strains produce high yields of simple lysergic acid derivatives. These include lysergic acid
α-hydroxyethylamide (Figure 103), lysergic acid amide (ergine) (Figure 99), which is also
an acid-catalysed decomposition product from lysergic acid α-hydroxyethylamide, and the
Δ
8,9-isomer of lysergic acid, paspalic acid (Figure 101). Lysergic acid is obtained from
the first two by hydrolysis, or from paspalic acid by allylic isomerization. Other alkaloids,
e.g. ergometrine and ergotamine, can then be produced semi-synthetically. High yielding
fermentation methods have also been developed for direct production of ergotamine and the
ergotoxine group of peptide alkaloids.
The pharmacologically active ergot alkaloids are based on (+)-lysergic acid (Figure 103),
but since one of the chiral centres in this compound (and its amide derivatives) is adjacent to
a carbonyl, the configuration at this centre can be changed as a result of enolization brought
about by heat or base (compare tropane alkaloids, page 298; again note that enolization
is favoured by conjugation with the aromatic ring). The new diastereomeric form of (+)-
lysergic acid is (+)-isolysergic acid (Figure 103), and alkaloids based on this compound are
effectively pharmacologically inactive. They are frequently found along with the (+)-lysergic
acid derivatives, amounts being significant if old ergot samples are processed, or unsuitable
isolation techniques are employed. In the biologically active lysergic acid derivatives, the
amide group occupies an 8-equatorial position, whilst in the inactive iso-forms, this group
is axial. However, the axial form is actually favoured because this configuration allows
hydrogen-bonding from the amide N-H to the hetrocyclic nitrogen at position 6. Derivatives
of (+)-isolysergic acid are named by adding the syllable
-in- to the corresponding (+)-lysergic
acid compound, e.g. ergometrinine, ergotaminine.
The ergot alkaloids owe their pharmacological activity to their ability to act at a-adrenergic,
dopaminergic and serotonergic receptors. The relationship of the general alkaloid structure
to those of noradrenaline, dopamine, and 5-hydroxytryptamine (5-HT, serotonin) is shown in
Figure 105. The pharmacological response may be complex. It depends on the preferred
receptor to which the compound binds, though all may be at least partially involved, and
whether the alkaloid is an agonist or antagonist.
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| Figure 105 |
Despite the unpleasant effects of ergot as manifested by St Anthony's Fire, whole ergot
preparations have been used since the 16th century to induce uterine contractions during
childbirth, and to reduce haemorrhage following the birth. This oxytocic effect (oxytocin is the
pituitary hormone that stimulates uterine muscle) is still medicinally valuable,
but is now achieved through use of the isolated alkaloid ergometrine. The deliberate use of
ergot to achieve abortions is dangerous and has led to fatalities.
Ergometrine (
ergonovine) (Figure 103) is used as an oxytocic, and is injected during the
final stages of labour and immediately following childbirth, especially if haemorrhage occurs.
Bleeding is reduced because of its vasoconstrictor effects, and it is valuable after Caesarian
operations. It is sometimes administered in combination with oxytocin itself.
Ergometrine is also orally active. It produces faster stimulation of uterine muscle than do
the other ergot alkaloids, and probably exerts its effect by acting on a-adrenergic receptors,
though it may also stimulate 5-HT receptors.
Ergotamine (Figure 103) is a partial agonist of α-adrenoceptors and 5-HT receptors.
It is not suitable for obstetric use because it also produces a pronounced peripheral
vasoconstrictor action. This property is exploited in the treatment of acute attacks of migraine,
where it reverses the dilatation of cranial blood vessels. Ergotamine is effective orally, or by
inhalation in aerosol form, and may be combined with caffeine, which is believed to enhance
its action. The semi-synthetic
dihydroergotamine is produced by hydrogenation of the
lysergic acid Δ
9,10 double bond (giving C-10 stereochemistry as in ergoline) and is claimed to
produce fewer side-effects, especially digestive upsets.
The 'ergotoxine' alkaloid mixture also has oxytocic and vasoconstrictor activity but is only
employed medicinally as the 9,10-dihydro derivatives
dihydroergotoxine (
co-dergocrine),
a mixture in equal proportions of
dihydroergocornine,
dihydroergocristine, and the
dihydroergocryptines (α- and β- in the ratio 2:1). In the case of these alkaloids, reduction of
the double bond appears to reverse the vasoconstrictor effect, and dihydroergotoxine has a
cerebral vasodilator activity. The increased blood flow is of benefit in some cases of senility
and mild dementia, and helps to improve both mental function and physical performance.
A number of semi-synthetic lysergic acid derivatives act by stimulation of dopamine receptors
in the brain, and are of value in the treatment of neurological disorders such as Parkinson's
disease.
Bromocriptine (2-bromo-α-ergocryptine),
cabergoline,
lisuride (
lysuride), and
pergolide(Figure 103) are all used in this way. Bromocriptine and cabergoline find wider
use in that they also inhibit release of prolactin by the pituitary, and can thus suppress lactation and be used in the treatment of breast tumours.
Methysergide
(Figure 103) is a semi-synthetic analogue of ergometrine, having a modified amino alcohol
side-chain and an N-methyl group on the indole ring. It is a potent 5-HT antagonist and as
such is employed in the prophylaxis of severe migraine headaches, though its administration
has to be very closely supervised.
Prolonged treatment with any of the ergot alkaloids is undesirable and it is vital that
the clinical features associated with ergot poisoning are recognized. Treatment must be
withdrawn immediately if any numbness or tingling develops in the fingers or toes. Sideeffects
will disappear on withdrawal of the drug, but there have been many cases where
misdiagnosis has unfortunately led to foot or toe rot, and the necessity for amputation of the
dead tissue.
Undoubtedly the most notorious of the lysergic acid derivatives is lysergide (lysergic
acid diethylamide or LSD) (Figure 103). This widely abused hallucinogen, known as
'acid', is probably the most active and specific psychotomimetic known, and is a mixed
agonist-anatagonist at 5-HT receptors, interfering with the normal processes. An effective
oral dose is from 30 to 50 �g. It was synthesized from lysergic acid, and even the trace amounts
absorbed during its handling were sufficient to give its creator quite dramatic hallucinations.
LSD intensifies perceptions and distorts them. How the mind is affected depends on how the
user is feeling at the time, and no two 'trips' are alike. Experiences can vary from beautiful
visions to living nightmares, sometimes lasting for days. Although the drug is not addictive, it
can lead to schizophrenia and there is danger of serious physical accidents occurring whilst
the user is under the influence of the drug.
Morning Glories
Lysergic acid derivatives have also been characterized in the seeds of morning glory (
Ipomoea
violacea),
Rivea corymbosa, and other members of the Convolvulaceae. Such seeds formed
the ancient hallucinogenic drug ololiuqui still used by the Mexican Indians in religious and
other ceremonies. Extracts from the ground seeds are swallowed and the narcotic and
hallucinogenic effects are said to provide contact with the gods. The active constituent has
been identified to be principally ergine (lysergic acid amide) (Figure 99), and this has an
activity about one-20th that of LSD, but is more narcotic than hallucinogenic. The alkaloid
content of the seeds is usually low, at about 0.05%, but higher levels (0.5-1.3%) have been
recorded. Minor ergot-related constituents include ergometrine (Figure 103), lysergic acid
α-hydroxyethylamide (Figure 103), the inactive isolysergic acid amide (erginine), and some
clavine alkaloids.
Since morning glories are widely cultivated ornamentals and seeds are readily available,
deliberate ingestion by thrill-seekers has been considerable. Although the biological activity
is well below that of LSD, the practice is potentially dangerous.