Download *Simple indole alkaloids include : melatonin, serotonin, psilocybin

Lecture 16
*Simple indole alkaloids include : melatonin, serotonin, psilocybin &
phytostigmine.
We discuss melatonin & serotonin in the last lecture.
3) psilocybin :
a hallucinogenic compound has been isolated from different Psilocybe species
these are a group of small mushrooms with worldwide distribution, Over 80
species of Psilocybe have been identified but not all of them contain this
hallucinogenic compound. The hallucinogenic activity is comparable to that of
mescaline (mescaline like effect), which means that it affect primarily the
auditory and ocular systems that causes visual hallucinations with rapidly
changing shapes and colours, different perceptions of space and time and
disorientation. The potency is similar to that of mescaline & up to 20 mg of
those mushrooms have to be ingested to observe this hallucination effects.
Psilocybin differ from serotonin that it has 4-OH(that is phosphorylated) not 5OH but it has similar activity. In addition it has 2 N-methyl groups. You should
be aware that methylation occur at the N in the side chain not in the N of the
ring.
The hallucinogenic activity of psilocybin is well known and it is prohibited by the
religious rules, and it was already known in the temperate regions because the
first utilization of these mushrooms for hallucinogenic purposes was from
Psilocybe semilanceata.
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4) physostigmine (eserine) :
Isolated from the seeds of the Physostigma venenosum ,this plant contain many
alkaloids but the most important one is physostigmine. Physostigmine is a very
unstable compound and should be kept in tightly closed containers because it
oxidized easily, with luck we can detect the deterioration of this compound by
the color change that occur due to oxidation therefore the oxidized derivative
(rubreserine) can be easily recognized by its red color.
In the structure of the amino acid tryptophan ( or its derivative tryptamine ),
there are 2 adjacent carbons ( the a & b carbons ) of the NH group inside the
indole ring, which are important nucleophilic centers because many of tryptophan
derivatives we are going to discuss are differing only in their substitutions,
either by a substitution or b substitution.
And in the case of physostigmine, it is just methylation of the b carbon, change
the position of the double bond then attack of the amino group in the side chain
to the a carbon forming a pyrrolidine ring, and this pyrrolidine ring is attached
to the indole ring therefore, in some references, it is considered as
pyrroleindole alkaloids based on the structure.
Then there is a 5-OH step that can be modified to form carbamate which is
very important to the activity of physostigmine and its related synthetic
analogues neostigmine & Pyridostigmine, so the activity of physostigmine is
primarily due to the carbamate part of the molecule.
Uses : physostigmine is the antidote for several anticholinergic compounds such
as atropine hyoscyamine and related substances as well as it is an antidote for
muscle relaxants like curare, moreover it is a transient (reversible) inhibitor of
acetylcholinesterase, which mean that it will cause accumulation of Ach and this
accumulation will enhance the memory & it is needed in the treatment of several
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disease like Alzheimer’s disease & Parkinson’s disease, this drug will not reverse
the disease but it will delay it. It can be useful also for the treatment of
glaucoma because of their capability of reducing intraocular pressure.
With this discussion of melatonin, serotonin, psilocybin & physostigmine we
complete the important representatives of simple derivatives of the amino acid
tryptophan which are primarily obtained by decarboxylation of the amino acid
tryptophan to obtain typtamine and then further modification especially
oxidation at position 4 or at position 5.
*Derivatives of tryptophan plus 2C units :
When we say 2C unit then we mean the presence of acetyl unit for the
modification of the biogenic amine tryptamine and here again we are coming to
the 2 positions; the a & b carbons.
Later on we will discuss tryptophan plus 5C and tryptophan plus 9C, and it is
exactly the same observation will be made regardless of the number of carbons
that is we need an active carbonyl group that can be obtained either by acetyl
coA (tryptophan plus 2C units) or from any aldehyde group (tryptophan plus 5C
and tryptophan plus 9C) to attach either the a or b carbons of the indole nucleus
then subsequent condensation of the amino group of the side chain.
When the a carbon is attacked, we will obtain a class of substances known as the
b carboline alkaloids regardless of the number of carbons of the attacking
carbonyl. Their structure is tricyclic possessing 2 N incorporated in the
heterocyclic ring but, unfortunately, this term is a little bit unexpected. When
the β carbon is attacked we will obtain indorenine alkaloids.
So the derivatives of the tryptophan plus 2C includes both b carboline alkaloids
& indorenine alkaloids. In this group we will mention 2 plants :
* Peganum harmala, which is abundant in Jordanian flora
* Paciflora incarnata, ornamental shrub easily recognized in the garden of the
houses, it is a climber with very nice spider like white-yellow florescent flowers ,
also occur in our area.
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These 2 plant representatives possess harman alkaloids; very closely related
compounds like harmine, harman & harmaline & these are b carboline alkaloids.
harman alkaloids are considered as sedative agents, in England it is
recommended, when the person can't sleep, should take some Paciflora flowers
in order to obtain this sedative effect.
Also it has been reported that these substances are useful in the treatment of
epilepsy and possessing anti-rheumatic activity. In Jordan the harman seeds are
used for the treatment of arthritis but of course it is not a safe plant because
it causes hallucinogenic effects, therefore it shouldn’t be used but,
unfortunately it is still widely used.
Derivative of Tryptophan +C2
β-Carbolin alkaloids (indole+Pyridine)
We use aldehyde C=O.
Ergot alkaloids ergoline:
Ergot alkaloids are isolated from infected plants (fungal infection).
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d-lysergic acid derivative: ends with ine
d-isolysergic acid derivative: ends with inine
Ergometrine obtained from d-lysergic acid (active form), but Ergometrinine
obtained from d-isolysergic acid (inactive form).
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The simplest amide of the lysergic acid is: Argine and Arginine. Arginine being
the inactive partner.
In the name, including the (-in) into the isolating compound would indicate that
we are dealing with the physiologically inactive partner.
* examples:
1. ergobasine - ergobasinine
2. ergometrine - ergometrinine
3. ergine - erginine
And so immediately we identify the amino acid involved in the formation of the
terminal compound.
Such similar questions are always put out regarding the name of the amino acid
contributing in the this type of compounds , the additional (-in) is added to
derivatives of the isolysergic acid.
Depending on the structure of the amide alkaloids or peptide alkaloids, we have
differences in their solubility.
We can obtain simple amide derivatives by the addition of simple ammonium or
short chain amino derivatives, like tropanolol for example, hence obtaining water
soluble derivatives while peptide alkaloids are water insoluble derivatives.
So how are these compounds formed?
from the combination or the symbiosis between the fungus and the plant, we are
collecting some plants which are formed during this evolution, which is so called
sclerotia.
- Sclerotia (plural) or sclerotium (singular)
In fact each fungi is propagating or growing or begin distributed binding of this
spores, and by the fungi we have: sexual spores and asexual spores.
The fungus Claviceps purpurea before the pollination time, attacks by
ascospores in the ovary of the poaceae plants in our specific case of the plant
which is (something) rye plant.
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And when the fungus attacks the ovary of the plant, this will produce vegetative
bodies of the fungus (within the ovary) and it's derivatives where it branches
its mycelium. Then it will produce its own spores, which will be suspended in the
honeydew of this mycelium. When insects attack, insect pollination will occur
using spores produced in the (something).
This type of spores are termed as the conidiospores, resecretion of this
conidiospores, and so the infection from the fungus prolong.
From the beginning the fungus shouldn't infect all the Poaceae, it us sufficient
only to the few plants which are already infected, immediately the mycelium will
form hyphae and the spores.
In fact pollination by wind or by insect primarily are digging in the
sweet honeydew infecting spores and other (something).
Part of the mycelium during late summer or early autumn will replace the
(something) oil, and it turns into a very hard dry mass, which is 1/2 cm, 45 mm
in diameter. So the ovary of the plant became brownish, hard masses. And these
brownish masses are originally formed by spores infection of ovaries of the
plant, which are called sclerotia.
In spring the sclerotia is collected (by hand) and submitted for the extraction.
Some sclerotia will produce its spores and the infection start a second start.
In the rye plants, the dark color red is preferred in expression of the central
vitamins (white is possible but red is more common). Also climatically, red is
more suitable.
In fact nowadays, thousands of red paper still react with alkaloids in their
biological activity depending on natural resources.
In central Europe different countries have thousands of hectors growing these
rye plants and artificially infecting this rye plant because the amount of
alkaloids is high. Natural infection is not sufficient to cover the work amount on
these alkaloids. And so artificially the ovaries of the plants will be infected by
the spores of the fungus. There are certain stages for this fungal growth
achieved in the lab, it is quite possible spores from the mycelium and
chonidiospores.
First infection will be by means of chonidiospores so when we produce
chonidiospores in the lab them all of the rye plants for the productions of the
ergot alkaloids can be artificially infected or exactly inoculated with this
conidiospores.
QUESTION: why can't we produce alkaloid if we have conidiospores?
The conidiospores can produce some of the alkaloids but not the important ones.
In order to produce the important ergot alkaloid we need rye plants, recent
studies have shown that -not only rye plants- but weed can also be used to be
infected by chonidiospores and replacement of the ovary by mycelium and
formation of lystic bodies.
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Sclerotium is defined in the dictionary as the resting body or the resting stage
of the fungus, and so in order to produce the important ergot alkaloids we need
the fungus at its resting stage. Fungus at any stage is not capable of producing
important alkaloids only at resting stage.
so when can the fungus reach the resting state?
when it infects the dry plant or Poaceae and forms (something) in the soil and
we'll collect these brownish masses by hand then submit it for the extraction of
these alkaloid.
- someone asked a question on whether we can only produce ergot alkaloids with
spores or not, here's what the doctor answered:
when we have sufficiently huge number of choniodiospores, then this
chonidiospores are either in each plant before pollination or this root formation
of the Poaceae by specific needle one by one each plant. Or multiple needle
containing devices which are being made nowadays, because it needs an attack, it
needs punctuation into the plant to insert the spores. When the spores are
inserted into the ovary, they will replace the (something), they replace the
completely formed mycelium.
As for insect infected plants, with ascospores mainly formed by pollination;
insect pollination. The plant will form brownish masses (cystic bodies) and it will
go down, remain in the soil till the early spring or winter -at this stage reaching
4 cm deep- will be collected.
In the past sclerotia couldn't be collected separately before introducing the
agriculture. In the pst anything from rye plants which would be collected would
get submitted to the production of the flour and bread-making. People who ate
this bread which is produced by fungus-infected flour will cause toxic symptoms.
Currently it is possible by sieving, by modern mill, separating (from poaceae) any
weed or rye plant from the sclerotia and healthy flour will be produced for the
production of the bread.
Chemistry of this compound:
It is a para of the 3,4 substituted indol ring. Positions 3 and 4 are needed for
the condensation of the Alergin alkaloid and what we are using is the C#5 in our
active isoquinine ring which is the DAPP.
- It starts with the condensation of C#4 with DAPP then side chain modification
of the indol by decaboxylation and the cyclization of the side chain, and here we
have the position for attack by DAPP, followed by the carboxylation of the
original carboxyl group and the methylation of the side chain and the nitrogen at
the CH3 of DAPP is oxidized to the level of the carboxyl group.
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-And this explains exactly why we are expecting, when we have CH3 group which
is oxidized then practically we will obtain two isomeric groups one of them will
be beta-carboxyl group and the other will be alpha-carboxyl group.
so, the simplest way to explain this is that:
condensation position of DAPP is very important with the indol. The cyclizationdecarboxylation- methylation- cyclization and oxidation of the CH3 of DAPP
group to the level of the carboxyl group and obtain D-lysergic acid or its isomer
isolysergic acid.
So, so far we have formed the compound with A/B/C/D and until we reach the
terminal compound we have different compounds.
* Important sites in the compound:
- Carboxyl group on C#8.
- Double bond between C#9 and C#10 by lysergic acid and isolysergic acid.
This compound can form other isomers:
- one isomer will be related to the carboxyl group, it is occurring in methyl.
** What kind of isomer can be formed ?
by changing the double bond position from C#9-C#10 position to another,
forming another isomer.
-Paspalic acid for example is one of the isomers of the lysergic acid.
* Isomerism within a structure is not restricted to positions of alpha and beta,
just shifting the double will yield isomeric compounds.
So the D lysergic acid and D isolysergic acid are not the only two possible
isomers, we have other isomers based on the position of the single double bond
in the ring (D). And one compound which has C#8-C#9 double bond is the
paspalic acid instead of C#9-C#10 in the lysergic acid.
In order to talk about ergot alkaloids we have to talk about derivatives of the
lysergic acid.
What kind of derivatives can we form? there are many agents, however our main
concern is the formation of the amides and formation of the peptides which are
important alkaloids of the lysergic acid.
In fact, the simplest derivative of the lysergic acid and isolysergic acid can be
obtained by : [ carboxylic group + ammonia ]. And the simplest amide derivative
obtained for the lysergic acid is ergine and its inactive partner erginine. It is
obtained by [lysergic acid + ammonia], we replace the hydroxyl group with amino
group then we have simple amide.
Ergine and Erginine are the simplest amides and the simplest amide derivatives
are water soluble, so their extraction from the plant material and from the
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sclerotia is easy because they are water soluble. And so they are cheap
compounds.
Ergine is not possessing the simplest amide carboxyl group replaced by amide
group is not a pharmaceutically potent compound.
- I apologize if the following compounds' names didn't make sense, I'm going to
write them the way I heard the doctor say their names :
- Pharmaceutically important compounds are:
Ergometrine which is two adesenomine and ergomanine and eglobasine.
Because different researches isolated same founds and each one gave mainly:
ergometrine, ergobasine, ergonomine. And the three are the same compound.
ergine is a non-pharmacologically important compound, but the Ergometrine
which happens to have other synonyms such as (ergonovine in the USA and
ergobasine in Switzerland), and it is an amide of lysergic acid
and 2-aminopropanol (3-carbon amino group); which is a naturally occuring
compund but swiss scientists have produced the synthitic derivatives is the
lysergic acid diethylamide (LSD), it is a simple ergine derivative by which the
nitrogen is beringed to 2 ethyl groups, which is a very potent hallocinic
compound.
***now the second group of the ergot alkaloids is the "Water in soluble" also
known as the "Ergopeptide alkaloids", which are the water insoluble derivatives
of the lysergic acid. we have the Ergotamine group which is used in the
treatment of migrain headaches,the ergoxine group,
and the ergotoxine group.
in this group a carboxyl group which is linked to a tripeptide. what we mean by a
tripeptide is that we have cyclic 3 amino acids linked together by a peptide
linkage and to a lyserginic acid, one of those amino acids is "Proline" always
found regrdless of the type of the water insoluble alkaloids, so constantly upun
hydrolysis we will get:
1) proline as one of the forming peptides of the tripeptide chain.
2) the other two amino acids can be either acyclic amino acids or aromatic
aminoacids.
3)3 ammonia cmpounds.
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4) lysirgenic acid.
* Ergot alkaloid's activities are different they may act as agonists or
antagonists, but the most important thing that they are dose dependent. this
activity can be noticed from the close symilarities in the structure between the
ergot alkaloids and the structure to those of noradrenaline, dopamine, and 5-HT
(serotonin), so they can fit into the receptor of the latter compounds and
emitate their activity ( α-adrenergic, dopaminergic, and serotonergic receptors).
which gives them their -dose dependent- very important biological activity. due
to their toxic effect such as the "Ergotism" their use must be limited and not
prolonged in order not to face any problems of toxicity.
the symptoms of Ergotism:
• GI distress, e.g. diarrhoea, abdominal pains, and vomiting.
• 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, the first and the most
common signs ergotism are tingling and loosing sensitivity of fingers .
• 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 doses of heavily 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.
*Ergometrine importance : it has been used since the
16th century to induce uterine contractions during childbirth and to reduce
haemorrhage following the birth. This oxytocic effect is still medicinally
valuable, but is now achieved through use of
the isolated alkaloid ergometrine. Ergometrine is used 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
valuableafter Caesarian operations. Ergometrine is also
orally active while oxitocine is only given parentrally. we have the semi-synthitic
type of ergometrine that has a longer duration and orally active.
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Methysergide is a semi-synthetic analogue of ergometrine having a modified
amino alcohol side-chaina nd an N-methyl group on the indole ring, is employed in
the prophylaxis of severe migraine headaches, because of its vasoconstrictive
properties.
*Ergotamine 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
atacks of migraine, where it reverses the dilatation of cranial blood vessels.
Dihydroergotamine is the semisynthetic derivative of ergotamine, as well as
Bromocriptine, cabergoline,
lisuride , and pergolide used for disorders such as Parkinson’s disease. they also
inhibit release of prolactin by the pituitary and can thus suppress lactation and
be used in the treatment of breast
tumours. we also have the lysergic acid derivatives is lysergide (lysergic acid
diethylamide or LSD) the most potent hilluciginic compound. An effective oral
dose is from 30 to 50 μg.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.
*Ergotoxine is another ergotamine compound that is used for the treatment of
dementia.
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GOOD LUCK
DONE BY :
Haya Odeh , Heba Jabr , Iba Alqasrawi, Huda Rustom
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