Indole alkaloids
Encyclopedia
Indole alkaloids are a class of alkaloids containing a structural moiety of indole
; many indole alkaloids also include isoprene
groups. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid
tryptophan
is the biochemical precursor of indole alkaloids.
s used the psilocybin mushroom
s which contain alkaloids psilocybin
and psilocin
. The flowering plant Rauwolfia serpentina
which contains reserpine
was a common medicine in India
around 1000 BC. Africans used the roots of the perennial rainforest
shrub Iboga, which contain ibogaine
, as a stimulant. An infusion of Calabar bean
seeds was given to people accused of crime in Nigeria
: its rejection by stomach was regarded as a sign of innocence, otherwise, the person was killed via the action of physostigmine
, which is present in the plant and which causes paralysis
of the heart and lungs.
Consumption of rye
and related cereal
s contaminated with the fungus
Claviceps purpurea
causes ergot
poisoning and ergotism
in humans and other mammals. The relationship between ergot and ergotism was established only in 1717, and the alkaloid ergotamine, one of the main active ingredients of ergot, was isolated in 1918.
The first indole alkaloid, strychnine
, was isolated by Pierre Joseph Pelletier
and Joseph Bienaimé Caventou
in 1818 from the plants of the Strychnos
genus. The correct structural formula
of strychnine was determined only in 1947, although the presence of strychnine in the structure of the indole nucleus was established somewhat earlier. Indole itself was first obtained by Adolf von Baeyer
in 1866 while decomposing Indigo
.
structural elements, synthesized by living organisms from dimethylallyl pyrophosphate
(DMAPP) and/or isopentenyl pyrophosphate
(IPP):
There are also purely structural classifications based on the presence of carbazole
, β-carboline or other units in the carbon skeleton of the alkaloid molecule. Some 200 dimeric indole alkaloids are known with two indole groups.
and 5-hydroxytryptamine (serotonin
). Although their assignment to the alkaloid is not universally accepted, they are both found in plants and animals. The tryptamine skeleton is part of the vast majority of indole alkaloids. So N,N-dimethyltryptamine
(DMT), psilocin
and its phosphorylated
psilocybin
also simplest derivatives of tryptamine. Some simple indole alkaloids do not contain tryptamine, such as gramine
and glycozoline (the latter is a derivative of carbazole
).
alkaloids is associated with the ease of forming the β-carboline core from tryptamine in the intramolecular Mannich reaction
. Simple (non-isoprenoid) β-carboline derivatives include harmine
, harmaline
, harmane and a slightly more complex structure of canthinone. Harmaline was first isolated in 1841 by Goegel and harmine in 1847 by Fritsche.
of indole nucleus at position 3 and the subsequent nucleophilic addition
at the carbon atom in positions 2 with the closure of the ethylamino group into a ring. A typical representative of this group is physostigmine
, which was isolated by Jobst and Hesse in 1864.
and isopentenyl pyrophosphate
.
alkaloids are a class of hemiterpenoid indole alkaloids related to lysergic acid
, which, in turn, is formed in a multistage reactions involving tryptophan
and DMAPP. Many ergot alkaloids are amides of lysergic acid. The simplest such amide is ergine
, and more complex can be distinguished into the following groups:
Ergotinine, discovered in 1875, and ergotoxine (1906) were subsequently proven to be a mixture of several alkaloids. In pure form, the first ergot alkaloids, ergotamine and its isomer ergotaminine were isolated by Arthur Stoll in 1918.
. Depending on the structure of this fragment, these alkaloids belong to Corynanthe, Iboga and Aspidosperma classes named by a typical genus or species of the plant which contain such alkaloids. The monoterpenoid part of their carbon skeletons are illustrated below on the example of alkaloids ajmalicine and catarantine. The circled carbon atoms are missing in the alkaloids which contain the C9 fragment instead of C10.
Corynanthe alkaloids include the unaltered skeleton of secologanin, which is modified in Iboga and Aspidosperma alkaloids. Some representatives monoterpenoid indole alkaloids:
There is also a small group of alkaloids present in the plant Aristotelia
– about 30 compounds, the most important of which is peduncularine – which contain a monoterpenoid C10 part originating not from secologanin.
Apart from bisindole alkaloids, dimeric alkaloids exist which are formed via dimerization of the indole monomer with another type of alkaloid. An example is tubulosine consisting of indole and isoquinoline
fragments.
(Peganum harmala), which contains harmane, harmine and harmaline, and Calabar bean
(Physostigma venenosum) containing physostigmine
. Some members of the family Convolvulaceae
, in particular Ipomoea violacea
and Turbina corymbosa, contain derivatives of lysergic acid. Despite the considerable structural diversity, most of monoterpenoid indole alkaloids is localized in three families of dicotyledon
plants: Apocynaceae
(genera Alstonia
, Aspidosperma
, Rauwolfia
and Catharanthus
), Rubiaceae
(Corynanthe) and Loganiaceae
(Strychnos
).
Indole alkaloids are also present in fungi. For example, members of the genus Psilocybe
contain simple derivatives of tryptamine and Claviceps are rich in derivatives of lysergic acid. The skin of many toad species of the Bufo
genus contains a derivative of tryptamine, bufotenine, and the skin and venom of the species Bufo alvarius (Colorado River Toad
) contains 5-MeO-DMT
. Serotonin
, which is an important neurotransmitter
in mammals, can also be attributed to simple indole alkaloids.
. For most of them, the first synthesis step is decarboxylation
of tryptophan to form tryptamine
. Dimethyltryptamine
(DMT) is formed from tryptamine by methylation
with the participation of coenzyme of S-adenosyl methionine
(SAM). Psilocin
is produced from dimethyltryptamine by oxidation and is then phosphorylated
into psilocybin
.
In the biosynthesis of serotonin, the intermediate product is not tryptamine but 5-hydroxytryptophan, which is in turn decarboxylated to form 5-hydroxytryptamine (serotonin).
Biosynthesis of β-carboline alkaloids occurs through the formation of Schiff base
from tryptamine and aldehyde
(or keto acid
) and subsequent intramolecular Mannich reaction
, where the C(2) carbon atom of indole serves as a nucleophile. Then, the aromaticity is restored via the loss of a proton at the C(2) atom. The resulting tetrahydro-β-carboline skeleton then gradually oxidizes to dihydro-β-carboline and β-carboline. In the formation of simple β-carboline alkaloids, such as harmine and harmaline, pyruvic acid
acts as the keto acid. In the synthesis of monoterpenoid indole alkaloids, secologanin
plays the role of the aldehyde. Pirroloindole alkaloids are synthesized in living organisms in a similar way.
Biosynthesis of ergot alkaloids begins with the alkylation of tryptophan by dimethylallyl pyrophosphate
(DMAPP), where the carbon atom C(4) in the indole nucleus plays the role of the nucleophile. The resulting 4-dimetilallil-L-tryptophan undergoes N-methylation. Further products of biosynthesis are chanoclavine-I and agroclavine – the latter is hydroxylated to elymoclavine, which in turn oxidizes into paspalic acid. In the process of allyl rearrangement, paspalic acid is converted to lysergic acid.
Biosynthesis of monoterpenoid indole alkaloids begins with the Mannich reaction of tryptamine and secologanin; it yields strictosidine which is converted to 4,21-dehydrogeissoschizine. Then, the biosynthesis of most alkaloids containing the unperturbed monoterpenoid part (Corynanthe type) proceeds through cyclization with the formation of cathenamine and subsequent reduction to ajmalicine in the presence of nicotinamide adenine dinucleotide phosphate
(NADPH). In the biosynthesis of other alkaloids, 4,21-dehydrogeissoschizine first converts into preaquamycin (an alkaloid of subtype strychnos, type Corynanthe) which gives rise to other alkaloids of subtype strychnos and of the types Iboga and Aspidosperma. Bisindole alkaloids vinblastine and vincristine
are produced in the reaction involving catarantine (alkaloid of type Iboga) and vindolin (type Aspidosperma).
and peripheral
nervous systems. Besides, bisindole alkaloids vinblastine and vincristine show antineoplastic effect.
Because of structural similarities with serotonin, many tryptamines can interact with serotonin 5-HT receptor
s. The main effect of the classical hallucinogens such as DMT
, psilocin, psilocybin and ibogaine is related to them being agonist
s of the 5-HT2A
receptors. In contrast, gramine is an antagonist of the 5-HT2A receptor.
Derivatives of lysergic acid include structural elements of both tryptamine and phenylethylamine and thus act on the whole group of the 5-HT receptors, adrenoceptors (mostly of type α) and dopamine receptors (mostly type D2). So ergotamine is a partial agonist
of α-adrenergic and 5-HT2 receptors, and thus narrows
blood vessels and stimulates constriction of the uterus
. Dihydroergotamine
is more selective to α-adrenergic receptors and has a weaker effect on serotonin receptors. Ergometrine is an agonist of α-adrenergic, 5-HT2 and partly D2 receptors. Compared with other ergot alkaloids, ergometrine has a greater selectivity in stimulating the uterus. LSD, a synthetic derivative of lysergic acid, is an agonist of 5-HT2A, 5-HT1A and to a lesser extent D2 receptors and has a powerful hallucinogenic effect.
Some monoterpenoid indole alkaloids also interact with adrenoceptors. For example, ajmalicine is a selective antagonist of α1-adrenergic receptors and therefore has antihypertensive action. Yohimbine
is more selective to α2 adrenoceptor; by blocking presynaptic α2-adrenoceptors, it increases the release of norepinephrine
thereby raising the blood pressure. Yohimbine was used for the treatment of erectile dysfunction
in men until emergence of more efficient drugs.
Some alkaloids affect the turnover of monoamines indirectly. So, harmine and harmaline are reversible selective inhibitors of monoamine oxidase-A
. Reserpine
reduces concentration of monoamines in presynaptic and synaptic
neurons, thereby inducing antihypertensive and antipsychotic effects.
Some indole alkaloids interact with other types of receptors. So, mitragynine
is an agonist of the μ-opioid receptor
. Harmal alkaloids are antagonists to the GABAA-receptor., and ibogaine
– to NMDA-receptors. Physostigmine
is a reversible acetylcholinesterase inhibitor
.
. Rauwolfia serpentina
, which contains reserpine as the active substance, was used for over 3000 years in India
to treat snake bites and insanity
. In medieval Europe, extracts of ergot
were used in medical abortion
.
Later, the plants were joined by pure preparations of indole alkaloids. Reserpine was the second (after chlorpromazine
) antipsychotic
drug; however, it showed relatively weak action and strong side effects, and is not used for this purpose any longer. Instead, it is prescribed as an antihypertensive drug, often in combination with other substances.
Other drugs that affect the cardiovascular system include ajmaline
, which is a Class I antiarrhythmic agents, and ajmalicine, which is used in Europe as an antihypertensive drug. Physostigmine – an inhibitor of acetylcholinesterase – and its synthetic analogs are used in the treatment of glaucoma
, Alzheimer's disease
(rivastigmine
) and myasthenia
(neostigmine
, pyridostigmine
, distigmine
). Ergot alkaloids ergometrine (ergobazin, ergonovine), ergotamine and their synthetic derivatives (methylergometrine) are applied against uterine bleeding, and bisindole alkaloids vinblastine and vincristine are antitumor agents.
Animal studies have shown that ibogaine
has a potential in treating heroin, cocaine
, and alcohol
addictions, which is associated with the ibogaine antagonism to NMDA-receptors. Medical use of ibogaine is hindered by its legal status, as it is banned in many countries as a powerful hallucinogenic drug with dangerous implications of overdose. However, illegal network in Europe
and United States
provide ibogaine for treating drug addiction.
Since ancient times, natural indole alkaloids were known as hallucinogens. Aztec
s used psilocybin mushroom
s, and the psychoactive infusion Ayahuasca
, made from such plants as Psychotria viridis
, Banisteriopsis caapi
and Ipomoea violacea
. Psychotria viridis is rich in the hallucinogen dimethyltryptamine
(DMT) and Banisteriopsis caapi contains much of β-carboline alkaloids (harmine, harmaline and tetrahydroharmine), which are monoamine oxidase inhibitor
s. It is believed that the main action of β-carbolines in Ayahuasca is to prevent the metabolization
of DMT in the digestive tract and liver
, so it can cross the blood-brain barrier
, whereas the direct effect of β-carbolines on the central nervous system is minimal. The poison of the toad toad, Bufo alvarius, was also used as a hallucinogen. One of the most common hallucinogenic drugs, lysergic acid diethylamide (LSD
), is a semi-synthetic tryptamine.
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...
; many indole alkaloids also include isoprene
Isoprene
Isoprene , or 2-methyl-1,3-butadiene, is a common organic compound with the formula CH2=CCH=CH2. Under standard conditions it is a colorless liquid...
groups. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
is the biochemical precursor of indole alkaloids.
History
The action of some indole alkaloids has been known for ages. AztecAztec
The Aztec people were certain ethnic groups of central Mexico, particularly those groups who spoke the Nahuatl language and who dominated large parts of Mesoamerica in the 14th, 15th and 16th centuries, a period referred to as the late post-classic period in Mesoamerican chronology.Aztec is the...
s used the psilocybin mushroom
Psilocybin mushroom
Psilocybin mushrooms are fungi that contain the psychoactive compounds psilocybin and psilocin. There are multiple colloquial terms for psilocybin mushrooms, the most common being shrooms or magic mushrooms....
s which contain alkaloids psilocybin
Psilocybin
Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...
and psilocin
Psilocin
Psilocin , an aromatic compound, sometimes also spelled psilocine, psilocyn, or psilotsin, is a psychedelic mushroom alkaloid. It is found in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin...
. The flowering plant Rauwolfia serpentina
Rauwolfia serpentina
Rauvolfia serpentina, or 'snakeroot' or 'sarpagandha' is a species of flowering plant in the family Apocynaceae.-Medicinal uses:It is one of the 50 fundamental herbs used in traditional Chinese medicine, where it has the name shégēn mù or yìndù shémù .Rauwolfia serpentina contains a number of...
which contains reserpine
Reserpine
Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely...
was a common medicine in India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
around 1000 BC. Africans used the roots of the perennial rainforest
Rainforest
Rainforests are forests characterized by high rainfall, with definitions based on a minimum normal annual rainfall of 1750-2000 mm...
shrub Iboga, which contain ibogaine
Ibogaine
Ibogaine is a naturally occurring psychoactive substance found in a number of plants, principally in a member of the Apocynaceae family known as Iboga . A hallucinogen with both psychedelic and dissociative properties, the substance is banned in some countries; in other countries it is being used...
, as a stimulant. An infusion of Calabar bean
Calabar bean
The Calabar bean is the seed of a leguminous plant, Physostigma venenosum, a native of tropical Africa, poisonous to humans. It derives the first part of its scientific name from a curious beak-like appendage at the end of the stigma, in the centre of the flower; this appendage, though solid, was...
seeds was given to people accused of crime in Nigeria
Nigeria
Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...
: its rejection by stomach was regarded as a sign of innocence, otherwise, the person was killed via the action of physostigmine
Physostigmine
Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
, which is present in the plant and which causes paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
of the heart and lungs.
Consumption of rye
Rye
Rye is a grass grown extensively as a grain and as a forage crop. It is a member of the wheat tribe and is closely related to barley and wheat. Rye grain is used for flour, rye bread, rye beer, some whiskeys, some vodkas, and animal fodder...
and related cereal
Cereal
Cereals are grasses cultivated for the edible components of their grain , composed of the endosperm, germ, and bran...
s contaminated with the fungus
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
Claviceps purpurea
Claviceps purpurea
Claviceps purpurea is a fungus that grows on the ears of rye and related cereal and forage plants. Consumption of grains or seeds contaminated with the fruiting structure of this fungus, the ergot sclerotium, can cause ergotism in humans and other mammals.. C...
causes ergot
Ergot
Ergot or ergot fungi refers to a group of fungi of the genus Claviceps. The most prominent member of this group is Claviceps purpurea. 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...
poisoning and ergotism
Ergotism
Ergotism is the effect of long-term ergot poisoning, traditionally due to the ingestion of the alkaloids produced by the Claviceps purpurea fungus which infects rye and other cereals, and more recently by the action of a number of ergoline-based drugs. It is also known as ergotoxicosis, ergot...
in humans and other mammals. The relationship between ergot and ergotism was established only in 1717, and the alkaloid ergotamine, one of the main active ingredients of ergot, was isolated in 1918.
The first indole alkaloid, strychnine
Strychnine
Strychnine is a highly toxic , colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion...
, was isolated by Pierre Joseph Pelletier
Pierre Joseph Pelletier
Pierre-Joseph Pelletier was a French chemist who did notable research on vegetable alkaloids, and was the co-discoverer of quinine and strychnine.- Further reading :...
and Joseph Bienaimé Caventou
Joseph Bienaimé Caventou
Joseph Bienaimé Caventou was a French chemist.He was a professor at the École de Pharmacie in Paris. He collaborated with Pierre-Joseph Pelletier in a Parisian laboratory located behind an apothecary. He was a pioneer in the use of mild solvents to isolate a number of active ingredients from...
in 1818 from the plants of the Strychnos
Strychnos
Strychnos is a genus of flowering plants, belonging to family Loganiaceae . The genus includes about 190 species of trees and lianas, distributed around the world's tropics....
genus. The correct structural formula
Structural formula
The structural formula of a chemical compound is a graphical representation of the molecular structure, showing how the atoms are arranged. The chemical bonding within the molecule is also shown, either explicitly or implicitly...
of strychnine was determined only in 1947, although the presence of strychnine in the structure of the indole nucleus was established somewhat earlier. Indole itself was first obtained by Adolf von Baeyer
Adolf von Baeyer
Johann Friedrich Wilhelm Adolf von Baeyer was a German chemist who synthesized indigo, and was the 1905 recipient of the Nobel Prize in Chemistry. Born in Berlin, he initially studied mathematics and physics at Berlin University before moving to Heidelberg to study chemistry with Robert Bunsen...
in 1866 while decomposing Indigo
Indigo
Indigo is a color named after the purple dye derived from the plant Indigofera tinctoria and related species. The color is placed on the electromagnetic spectrum between about 420 and 450 nm in wavelength, placing it between blue and violet...
.
Classification
Depending on their biosynthesis, two types of indole alkaloids are distinguished; isoprenoids and non-isoprenoids. The latter include terpenoidTerpenoid
The terpenoids , sometimes called isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures that differ from one another not only in...
structural elements, synthesized by living organisms from dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate is an intermediate product of both mevalonic acid pathway and DOXP/MEP pathway. It is an isomer of isopentenyl pyrophosphate and exists in virtually all life forms...
(DMAPP) and/or isopentenyl pyrophosphate
Isopentenyl pyrophosphate
Isopentenyl pyrophosphate is an intermediate in the classical, HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes and terpenoids. IPP is formed from acetyl-CoA via mevalonic acid...
(IPP):
- Non-isoprenoid:
- Simple derivatives of indoleIndoleIndole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...
- Simple derivatives of β-carboline
- Pyrroloindole alkaloids
- Simple derivatives of indole
- Isoprenoid:
- hemiterpenoidsTerpeneTerpenes are a large and diverse class of organic compounds, produced by a variety of plants, particularly conifers, though also by some insects such as termites or swallowtail butterflies, which emit terpenes from their osmeterium. They are often strong smelling and thus may have had a protective...
: ergot alkaloids - monoterpenoidsMonoterpeneMonoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear or contain rings...
.
- hemiterpenoids
There are also purely structural classifications based on the presence of carbazole
Carbazole
Carbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two six-membered benzene ring fused on either side of a five-membered nitrogen-containing ring...
, β-carboline or other units in the carbon skeleton of the alkaloid molecule. Some 200 dimeric indole alkaloids are known with two indole groups.
Non-isoprenoid indole alkaloids
The number of known non-isoprenoid indole alkaloids is small compared to the number of indole alkaloids.Simple indole derivatives
One of the simplest and yet widespread indole derivatives are the biogenic amines tryptamineTryptamine
Tryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...
and 5-hydroxytryptamine (serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
). Although their assignment to the alkaloid is not universally accepted, they are both found in plants and animals. The tryptamine skeleton is part of the vast majority of indole alkaloids. So N,N-dimethyltryptamine
Dimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
(DMT), psilocin
Psilocin
Psilocin , an aromatic compound, sometimes also spelled psilocine, psilocyn, or psilotsin, is a psychedelic mushroom alkaloid. It is found in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin...
and its phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
psilocybin
Psilocybin
Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...
also simplest derivatives of tryptamine. Some simple indole alkaloids do not contain tryptamine, such as gramine
Gramine
Gramine is a naturally occurring indole alkaloid present in several plant species. Gramine may play a defensive role in these plants, since it is toxic to many organisms.-Occurrence:...
and glycozoline (the latter is a derivative of carbazole
Carbazole
Carbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two six-membered benzene ring fused on either side of a five-membered nitrogen-containing ring...
).
Simple derivatives of β-carboline
The prevalence of β-carbolineBeta-carboline
β-Carboline is an organic amine that is the prototype of a class of compounds known as β-carbolines.-Pharmacology:...
alkaloids is associated with the ease of forming the β-carboline core from tryptamine in the intramolecular Mannich reaction
Mannich reaction
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...
. Simple (non-isoprenoid) β-carboline derivatives include harmine
Harmine
Harmine is a fluorescent harmala alkaloid belonging to the beta-carboline family of compounds. It occurs in a number of different plants, most notably the Middle Eastern plant harmal or Syrian rue and the South American vine Banisteriopsis caapi...
, harmaline
Harmaline
Harmaline is a fluorescent psychoactive indole alkaloid from the group of harmala alkaloids and beta-carbolines. It is the reduced hydrogenated form of harmine.-Occurrence in nature:...
, harmane and a slightly more complex structure of canthinone. Harmaline was first isolated in 1841 by Goegel and harmine in 1847 by Fritsche.
Pyrolo-indole alkaloids
Pyrolo-indole alkaloids form a relatively small group of tryptamine derivatives. They are produced by methylationMethylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
of indole nucleus at position 3 and the subsequent nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
at the carbon atom in positions 2 with the closure of the ethylamino group into a ring. A typical representative of this group is physostigmine
Physostigmine
Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
, which was isolated by Jobst and Hesse in 1864.
Isoprenoid indole alkaloids
Isoprenoid indole alkaloids include residues of tryptophan or tryptamine and isoprenoid building blocks derived from the dimethylallyl pyrophosphateDimethylallyl pyrophosphate
Dimethylallyl pyrophosphate is an intermediate product of both mevalonic acid pathway and DOXP/MEP pathway. It is an isomer of isopentenyl pyrophosphate and exists in virtually all life forms...
and isopentenyl pyrophosphate
Isopentenyl pyrophosphate
Isopentenyl pyrophosphate is an intermediate in the classical, HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes and terpenoids. IPP is formed from acetyl-CoA via mevalonic acid...
.
Ergot alkaloids
ErgotErgot
Ergot or ergot fungi refers to a group of fungi of the genus Claviceps. The most prominent member of this group is Claviceps purpurea. 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...
alkaloids are a class of hemiterpenoid indole alkaloids related to lysergic acid
Lysergic acid
Lysergic acid, also known as D-lysergic acid and -lysergic acid, is a precursor for a wide range of ergoline alkaloids that are produced by the ergot fungus and some plants. Amides of lysergic acid, lysergamides, are widely used as pharmaceuticals and as psychedelic drugs...
, which, in turn, is formed in a multistage reactions involving tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
and DMAPP. Many ergot alkaloids are amides of lysergic acid. The simplest such amide is ergine
Ergine
Ergine, also known as d-lysergic acid amide , d-lysergamide, and LA-111, is an alkaloid of the ergoline family that occurs in various species of vines of the Convolvulaceae and some species of fungi...
, and more complex can be distinguished into the following groups:
- Water-soluble aminoalcohol derivatives, such as ergometrine and its isomerIsomerIn chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
ergometrinine - Water-insoluble polypeptide derivatives:
- Ergotamine group, including ergotamine, ergosine and their isomers
- Ergoxine groups, including ergostine, ergoptine, ergonine and their isomers
- Ergotoxine group, including ergocristineErgocristineErgocristine is an ergopeptine and one of the ergot alkaloids.It was used as precursor in the manufacture of LSD as an alternative for the controlled substances ergotamine and ergometrine by various LSD manufacturers, including William Leonard Pickard...
, α-ergocryptineErgocryptineErgocryptine is an ergopeptine and one of the ergot alkaloids. It is often used to synthesis LSD, rather than ergotamine. It was the precursor being used by William Leonard Pickard in his clandestine LSD lab....
, β-ergocryptine, ergocornine and their isomers.
Ergotinine, discovered in 1875, and ergotoxine (1906) were subsequently proven to be a mixture of several alkaloids. In pure form, the first ergot alkaloids, ergotamine and its isomer ergotaminine were isolated by Arthur Stoll in 1918.
Monoterpenoids
Most monoterpenoid alkaloids included a C9 or C10 fragment originating from the secologaninSecologanin
Secologanin is a monoterpene synthesized from geranyl pyrophosphate in the mevalonate pathway. Secologanin then proceedes with dopamine to form ipecac alkaloids.-Biosynthesis:...
. Depending on the structure of this fragment, these alkaloids belong to Corynanthe, Iboga and Aspidosperma classes named by a typical genus or species of the plant which contain such alkaloids. The monoterpenoid part of their carbon skeletons are illustrated below on the example of alkaloids ajmalicine and catarantine. The circled carbon atoms are missing in the alkaloids which contain the C9 fragment instead of C10.
Corynanthe alkaloids include the unaltered skeleton of secologanin, which is modified in Iboga and Aspidosperma alkaloids. Some representatives monoterpenoid indole alkaloids:
| Type | Number of carbon atoms in the monoterpenoid fragment | |
|---|---|---|
| C9 | C10 | |
| Corynanthe | Ajmaline Ajmaline Ajmaline is a class Ia antiarrhythmic agent. It is often used to bring out typical findings of ST elevations in patients suspected of having Brugada syndrome.... , aquamycin, strychnine Strychnine Strychnine is a highly toxic , colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion... , brucine Brucine Brucine is a bitter alkaloid closely related to strychnine. It occurs in several plant species, the most well known being the Strychnos nux-vomica tree, found in South-East Asia.While brucine is related to strychnine, it is not as poisonous... |
Ajmalicine, yohimbine Yohimbine Yohimbine is an alkaloid with stimulant and aphrodisiac effects found naturally in Pausinystalia yohimbe . It is also found naturally in Rauwolfia serpentina , Alchornea floribunda , along with several other active alkaloids... , reserpine Reserpine Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely... , sarpagin, mitragynine Mitragynine Mitragynine, an indole alkaloid, is the most abundant active alkaloid in the plant Mitragyna speciosa, commonly known as Kratom.-Pharmacology:... |
| Iboga | Ibogaine Ibogaine Ibogaine is a naturally occurring psychoactive substance found in a number of plants, principally in a member of the Apocynaceae family known as Iboga . A hallucinogen with both psychedelic and dissociative properties, the substance is banned in some countries; in other countries it is being used... , ibogamin |
Voacangine Voacangine Voacangine is an alkaloid found predominantly in the rootbark of the Voacanga africana tree, as well as in other plants such as Tabernanthe iboga, Tabernaemontana africana, Trachelospermum jasminoides and Ervatamia yunnanensis... |
| Aspidosperma | Eburnamin | Tabersonine, vindolin, vincamine Vincamine Vincamine is a peripheral vasodilator that increases blood flow to the brain . Generic drugs containing vincamine exist in specific regions. Most common drug preparations are in the sustained release forms... |
There is also a small group of alkaloids present in the plant Aristotelia
Aristotelia (plant)
Aristotelia is a genus with 18 species, of tree in the family Elaeocarpaceae. It is named in honor of the Greek philosopher Aristoteles.- Species :*Aristotelia australasica*Aristotelia braithwaitei*Aristotelia fruticosa...
– about 30 compounds, the most important of which is peduncularine – which contain a monoterpenoid C10 part originating not from secologanin.
Bisindole alkaloids
More than 200 of dimeric indole (bisindole) alkaloids are known. They are produced in living organisms through dimerization of monomeric indole bases, in the following reactions:- Mannich reactionMannich reactionThe Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...
(voacamine) - Michael reactionMichael reactionThe Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
(villalstonine) - CondensationCondensation reactionA condensation reaction is a chemical reaction in which two molecules or moieties combine to form one single molecule, together with the loss of a small molecule. When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride,...
of aldehydeAldehydeAn aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
s with amineAmineAmines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
s (toxiferineToxiferineToxiferine is a curare toxin. It is a nicotinic acetylcholine receptor antagonist....
, calebassine - Oxidative coupling of tryptamines (calicantine);
- Splitting of the functional group of one of the monomers (vinblastineVinblastineVinblastine is an antimicrotubule drug used to treat certain kinds of cancer, including Hodgkin's lymphoma, non-small cell lung cancer, breast cancer, head and neck cancer, and testicular cancer. It is also used to treat Langerhan cell histiocytosis....
, vincristineVincristineVincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
).
| Voacamine Voacamine Voacamine, also known under the older names voacanginine and vocamine, is a naturally occurring dimeric indole alkaloid of the secologanin type, found in a number of plants, including Voacanga africana.- Chemical structure :... |
Villalstonine | Toxiferine Toxiferine Toxiferine is a curare toxin. It is a nicotinic acetylcholine receptor antagonist.... |
Vinblastine Vinblastine Vinblastine is an antimicrotubule drug used to treat certain kinds of cancer, including Hodgkin's lymphoma, non-small cell lung cancer, breast cancer, head and neck cancer, and testicular cancer. It is also used to treat Langerhan cell histiocytosis.... |
Apart from bisindole alkaloids, dimeric alkaloids exist which are formed via dimerization of the indole monomer with another type of alkaloid. An example is tubulosine consisting of indole and isoquinoline
Isoquinoline
Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline...
fragments.
Distribution in nature
The plants that are rich in non-isoprenoid indole alkaloids include harmalHarmal
Harmal is a plant of the family Nitrariaceae, native from the eastern Mediterranean region east to India. It is also known as Wild Rue or Syrian Rue because of its resemblance to plants of the rue family....
(Peganum harmala), which contains harmane, harmine and harmaline, and Calabar bean
Calabar bean
The Calabar bean is the seed of a leguminous plant, Physostigma venenosum, a native of tropical Africa, poisonous to humans. It derives the first part of its scientific name from a curious beak-like appendage at the end of the stigma, in the centre of the flower; this appendage, though solid, was...
(Physostigma venenosum) containing physostigmine
Physostigmine
Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
. Some members of the family Convolvulaceae
Convolvulaceae
Convolvulaceae, known commonly as the bindweed or morning glory family, are a group of about 60 genera and more than 1,650 species of mostly herbaceous vines, but also trees, shrubs and herbs.- Description :...
, in particular Ipomoea violacea
Ipomoea violacea
Ipomoea violacea is a perennial species of Ipomoea that occurs throughout the tropics, growing in coastal regions. It is most commonly called 'Beach Moonflower' or 'Sea Moonflower' as the flowers open at night...
and Turbina corymbosa, contain derivatives of lysergic acid. Despite the considerable structural diversity, most of monoterpenoid indole alkaloids is localized in three families of dicotyledon
Dicotyledon
The dicotyledons, also known as dicots, are a group of flowering plants whose seed typically has two embryonic leaves or cotyledons. There are around 199,350 species within this group...
plants: Apocynaceae
Apocynaceae
The Apocynaceae or dogbane family is a family of flowering plants that includes trees, shrubs, herbs, and lianas.Many species are tall trees found in tropical rainforests, and most are from the tropics and subtropics, but some grow in tropical dry, xeric environments. There are also perennial herbs...
(genera Alstonia
Alstonia
Alstonia is a widespread genus of evergreen trees and shrubs from the dogbane family . It was named by Robert Brown in 1811, after Charles Alston , Professor of botany at Edinburgh from 1716-1760....
, Aspidosperma
Aspidosperma
Aspidosperma is a genus of flowering plant in the family Apocynaceae.Species include:*Aspidosperma curranii*Aspidosperma cylindrocarpon*Aspidosperma darienense*Aspidosperma dasycarpon*Aspidosperma discolor...
, Rauwolfia
Rauwolfia
Rauvolfia is a genus of evergreen trees and shrubs in the dogbane family, Apocynaceae. The genus is named to honor Leonhard Rauwolf. The approximately 85 species in the genus can mainly be found in tropical regions...
and Catharanthus
Catharanthus
Catharanthus is a genus of eight species of herbaceous perennial plants, six endemic to the island of Madagascar, the seventh and eighth native to the Indian subcontinent in southern Asia...
), Rubiaceae
Rubiaceae
The Rubiaceae is a family of flowering plants, variously called the coffee family, madder family, or bedstraw family. The group contains many commonly known plants, including the economically important coffee , quinine , and gambier , and the horticulturally valuable madder , west indian jasmine ,...
(Corynanthe) and Loganiaceae
Loganiaceae
Loganiaceae are a family of flowering plants classified in order Gentianales. The family includes 13 genera, distributed around the world's tropics.Earlier treatments of the family have included up to 29 genera...
(Strychnos
Strychnos
Strychnos is a genus of flowering plants, belonging to family Loganiaceae . The genus includes about 190 species of trees and lianas, distributed around the world's tropics....
).
Indole alkaloids are also present in fungi. For example, members of the genus Psilocybe
Psilocybe
Psilocybe is a genus of small mushrooms growing worldwide. This genus is best known for its species with psychedelic or hallucinogenic properties, widely known as "magic mushrooms", though the majority of species do not contain hallucinogenic compounds...
contain simple derivatives of tryptamine and Claviceps are rich in derivatives of lysergic acid. The skin of many toad species of the Bufo
Bufo
Bufo is a large genus of about 150 species of true toads in the amphibian family Bufonidae. Bufo is a Latin word for toad.- Description :...
genus contains a derivative of tryptamine, bufotenine, and the skin and venom of the species Bufo alvarius (Colorado River Toad
Colorado River Toad
The Colorado River toad, Bufo alvarius, also known as the Sonoran Desert toad, is a psychoactive toad found in northern Mexico and the southwestern United States...
) contains 5-MeO-DMT
5-MeO-DMT
5-MeO-DMT is a powerful psychedelic tryptamine. It is found in a wide variety of plant and psychoactive toad species and, like its close relatives DMT and bufotenin , it has been used as an entheogen by South American shamans for thousands of years.-Chemistry:5-MeO-DMT was first synthesized in...
. Serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, which is an important neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in mammals, can also be attributed to simple indole alkaloids.
Biosynthesis
Biogenetic precursor of all indole alkaloids is the amino acid tryptophanTryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
. For most of them, the first synthesis step is decarboxylation
Decarboxylation
Decarboxylation is a chemical reaction that releases carbon dioxide . Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carbonation, the addition of CO2 to...
of tryptophan to form tryptamine
Tryptamine
Tryptamine is a monoamine alkaloid found in plants, fungi, and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived...
. Dimethyltryptamine
Dimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
(DMT) is formed from tryptamine by methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
with the participation of coenzyme of S-adenosyl methionine
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
(SAM). Psilocin
Psilocin
Psilocin , an aromatic compound, sometimes also spelled psilocine, psilocyn, or psilotsin, is a psychedelic mushroom alkaloid. It is found in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin...
is produced from dimethyltryptamine by oxidation and is then phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
into psilocybin
Psilocybin
Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...
.
In the biosynthesis of serotonin, the intermediate product is not tryptamine but 5-hydroxytryptophan, which is in turn decarboxylated to form 5-hydroxytryptamine (serotonin).
Biosynthesis of β-carboline alkaloids occurs through the formation of Schiff base
Schiff base
A Schiff base, named after Hugo Schiff, is a compound with a functional group that contains a carbon-nitrogen double bond with the nitrogen atom connected to an aryl or alkyl group, not hydrogen....
from tryptamine and aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
(or keto acid
Keto acid
Keto acids are organic compounds that contain a carboxylic acid group and a ketone group. The alpha-keto acids are especially important in biology as they are involved in the Krebs citric acid cycle and in glycolysis...
) and subsequent intramolecular Mannich reaction
Mannich reaction
The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound also known as a Mannich base...
, where the C(2) carbon atom of indole serves as a nucleophile. Then, the aromaticity is restored via the loss of a proton at the C(2) atom. The resulting tetrahydro-β-carboline skeleton then gradually oxidizes to dihydro-β-carboline and β-carboline. In the formation of simple β-carboline alkaloids, such as harmine and harmaline, pyruvic acid
Pyruvic acid
Pyruvic acid is an organic acid, a ketone, as well as the simplest of the alpha-keto acids. The carboxylate ion of pyruvic acid, CH3COCOO−, is known as pyruvate, and is a key intersection in several metabolic pathways....
acts as the keto acid. In the synthesis of monoterpenoid indole alkaloids, secologanin
Secologanin
Secologanin is a monoterpene synthesized from geranyl pyrophosphate in the mevalonate pathway. Secologanin then proceedes with dopamine to form ipecac alkaloids.-Biosynthesis:...
plays the role of the aldehyde. Pirroloindole alkaloids are synthesized in living organisms in a similar way.
Biosynthesis of ergot alkaloids begins with the alkylation of tryptophan by dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate is an intermediate product of both mevalonic acid pathway and DOXP/MEP pathway. It is an isomer of isopentenyl pyrophosphate and exists in virtually all life forms...
(DMAPP), where the carbon atom C(4) in the indole nucleus plays the role of the nucleophile. The resulting 4-dimetilallil-L-tryptophan undergoes N-methylation. Further products of biosynthesis are chanoclavine-I and agroclavine – the latter is hydroxylated to elymoclavine, which in turn oxidizes into paspalic acid. In the process of allyl rearrangement, paspalic acid is converted to lysergic acid.
Biosynthesis of monoterpenoid indole alkaloids begins with the Mannich reaction of tryptamine and secologanin; it yields strictosidine which is converted to 4,21-dehydrogeissoschizine. Then, the biosynthesis of most alkaloids containing the unperturbed monoterpenoid part (Corynanthe type) proceeds through cyclization with the formation of cathenamine and subsequent reduction to ajmalicine in the presence of nicotinamide adenine dinucleotide phosphate
Nicotinamide adenine dinucleotide phosphate
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or TPN in older notation , is a coenzyme used in anabolic reactions, such as lipid and nucleic acid synthesis, which require NADPH as a reducing agent....
(NADPH). In the biosynthesis of other alkaloids, 4,21-dehydrogeissoschizine first converts into preaquamycin (an alkaloid of subtype strychnos, type Corynanthe) which gives rise to other alkaloids of subtype strychnos and of the types Iboga and Aspidosperma. Bisindole alkaloids vinblastine and vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
are produced in the reaction involving catarantine (alkaloid of type Iboga) and vindolin (type Aspidosperma).
Physiological activity
Indole alkaloids act on the centralCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and peripheral
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
nervous systems. Besides, bisindole alkaloids vinblastine and vincristine show antineoplastic effect.
Because of structural similarities with serotonin, many tryptamines can interact with serotonin 5-HT receptor
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
s. The main effect of the classical hallucinogens such as DMT
Dimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
, psilocin, psilocybin and ibogaine is related to them being agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s of the 5-HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
receptors. In contrast, gramine is an antagonist of the 5-HT2A receptor.
Derivatives of lysergic acid include structural elements of both tryptamine and phenylethylamine and thus act on the whole group of the 5-HT receptors, adrenoceptors (mostly of type α) and dopamine receptors (mostly type D2). So ergotamine is a partial agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
of α-adrenergic and 5-HT2 receptors, and thus narrows
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
blood vessels and stimulates constriction of the uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
. Dihydroergotamine
Dihydroergotamine
Dihydroergotamine is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan...
is more selective to α-adrenergic receptors and has a weaker effect on serotonin receptors. Ergometrine is an agonist of α-adrenergic, 5-HT2 and partly D2 receptors. Compared with other ergot alkaloids, ergometrine has a greater selectivity in stimulating the uterus. LSD, a synthetic derivative of lysergic acid, is an agonist of 5-HT2A, 5-HT1A and to a lesser extent D2 receptors and has a powerful hallucinogenic effect.
Some monoterpenoid indole alkaloids also interact with adrenoceptors. For example, ajmalicine is a selective antagonist of α1-adrenergic receptors and therefore has antihypertensive action. Yohimbine
Yohimbine
Yohimbine is an alkaloid with stimulant and aphrodisiac effects found naturally in Pausinystalia yohimbe . It is also found naturally in Rauwolfia serpentina , Alchornea floribunda , along with several other active alkaloids...
is more selective to α2 adrenoceptor; by blocking presynaptic α2-adrenoceptors, it increases the release of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
thereby raising the blood pressure. Yohimbine was used for the treatment of erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
in men until emergence of more efficient drugs.
Some alkaloids affect the turnover of monoamines indirectly. So, harmine and harmaline are reversible selective inhibitors of monoamine oxidase-A
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
. Reserpine
Reserpine
Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely...
reduces concentration of monoamines in presynaptic and synaptic
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
neurons, thereby inducing antihypertensive and antipsychotic effects.
Some indole alkaloids interact with other types of receptors. So, mitragynine
Mitragynine
Mitragynine, an indole alkaloid, is the most abundant active alkaloid in the plant Mitragyna speciosa, commonly known as Kratom.-Pharmacology:...
is an agonist of the μ-opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
. Harmal alkaloids are antagonists to the GABAA-receptor., and ibogaine
Ibogaine
Ibogaine is a naturally occurring psychoactive substance found in a number of plants, principally in a member of the Apocynaceae family known as Iboga . A hallucinogen with both psychedelic and dissociative properties, the substance is banned in some countries; in other countries it is being used...
– to NMDA-receptors. Physostigmine
Physostigmine
Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
is a reversible acetylcholinesterase inhibitor
Acetylcholinesterase inhibitor
An acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...
.
Applications
Plants and fungi that contain indole alkaloids have a long history of use in traditional medicineTraditional medicine
Traditional medicine comprises unscientific knowledge systems that developed over generations within various societies before the era of modern medicine...
. Rauwolfia serpentina
Rauwolfia serpentina
Rauvolfia serpentina, or 'snakeroot' or 'sarpagandha' is a species of flowering plant in the family Apocynaceae.-Medicinal uses:It is one of the 50 fundamental herbs used in traditional Chinese medicine, where it has the name shégēn mù or yìndù shémù .Rauwolfia serpentina contains a number of...
, which contains reserpine as the active substance, was used for over 3000 years in India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
to treat snake bites and insanity
Insanity
Insanity, craziness or madness is a spectrum of behaviors characterized by certain abnormal mental or behavioral patterns. Insanity may manifest as violations of societal norms, including becoming a danger to themselves and others, though not all such acts are considered insanity...
. In medieval Europe, extracts of ergot
Ergot
Ergot or ergot fungi refers to a group of fungi of the genus Claviceps. The most prominent member of this group is Claviceps purpurea. 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...
were used in medical abortion
Medical abortion
A medical abortion is a type of non-surgical abortion in which abortifacient pharmaceutical drugs are used to induce abortion. An oral preparation for medical abortion is commonly referred to as an abortion pill....
.
Later, the plants were joined by pure preparations of indole alkaloids. Reserpine was the second (after chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...
) antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
drug; however, it showed relatively weak action and strong side effects, and is not used for this purpose any longer. Instead, it is prescribed as an antihypertensive drug, often in combination with other substances.
Other drugs that affect the cardiovascular system include ajmaline
Ajmaline
Ajmaline is a class Ia antiarrhythmic agent. It is often used to bring out typical findings of ST elevations in patients suspected of having Brugada syndrome....
, which is a Class I antiarrhythmic agents, and ajmalicine, which is used in Europe as an antihypertensive drug. Physostigmine – an inhibitor of acetylcholinesterase – and its synthetic analogs are used in the treatment of glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(rivastigmine
Rivastigmine
Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which...
) and myasthenia
Myasthenia
-Medical conditions:* Myasthenia gravis* Ocular myasthenia* Lambert-Eaton myasthenic syndrome...
(neostigmine
Neostigmine
Neostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.- Synthesis :Neostigmine was first synthesized by Aeschlimann and Reinert in 1931....
, pyridostigmine
Pyridostigmine
Pyridostigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. Since it is a quaternary amine, it is poorly absorbed in the gut and does not cross the blood-brain barrier, except possibly in stressful conditions.-Mode of action:...
, distigmine
Distigmine
Distigmine is a parasympathomimetic. Distigmine is similar to pyridostigmine and neostigmine but has a longer duration of action. It is available as tablets on prescription only...
). Ergot alkaloids ergometrine (ergobazin, ergonovine), ergotamine and their synthetic derivatives (methylergometrine) are applied against uterine bleeding, and bisindole alkaloids vinblastine and vincristine are antitumor agents.
Animal studies have shown that ibogaine
Ibogaine
Ibogaine is a naturally occurring psychoactive substance found in a number of plants, principally in a member of the Apocynaceae family known as Iboga . A hallucinogen with both psychedelic and dissociative properties, the substance is banned in some countries; in other countries it is being used...
has a potential in treating heroin, cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, and alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
addictions, which is associated with the ibogaine antagonism to NMDA-receptors. Medical use of ibogaine is hindered by its legal status, as it is banned in many countries as a powerful hallucinogenic drug with dangerous implications of overdose. However, illegal network in Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
and United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
provide ibogaine for treating drug addiction.
Since ancient times, natural indole alkaloids were known as hallucinogens. Aztec
Aztec
The Aztec people were certain ethnic groups of central Mexico, particularly those groups who spoke the Nahuatl language and who dominated large parts of Mesoamerica in the 14th, 15th and 16th centuries, a period referred to as the late post-classic period in Mesoamerican chronology.Aztec is the...
s used psilocybin mushroom
Psilocybin mushroom
Psilocybin mushrooms are fungi that contain the psychoactive compounds psilocybin and psilocin. There are multiple colloquial terms for psilocybin mushrooms, the most common being shrooms or magic mushrooms....
s, and the psychoactive infusion Ayahuasca
Ayahuasca
Ayahuasca is any of various psychoactive infusions or decoctions prepared from the Banisteriopsis spp. vine, usually mixed with the leaves of dimethyltryptamine-containing species of shrubs from the Psychotria genus...
, made from such plants as Psychotria viridis
Psychotria viridis
Psychotria viridis is a shrub from the coffee family, Rubiaceae. It has many local names, including Chacruna and Chacrona ....
, Banisteriopsis caapi
Banisteriopsis caapi
Banisteriopsis caapi, also known as Ayahuasca, Caapi or Yage, is a South American jungle vine of the family Malpighiaceae. It is used to prepare Ayahuasca, a decoction that has a long history of entheogenic uses as a medicine and "plant teacher" among the indigenous peoples of the Amazon Rainforest...
and Ipomoea violacea
Ipomoea violacea
Ipomoea violacea is a perennial species of Ipomoea that occurs throughout the tropics, growing in coastal regions. It is most commonly called 'Beach Moonflower' or 'Sea Moonflower' as the flowers open at night...
. Psychotria viridis is rich in the hallucinogen dimethyltryptamine
Dimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
(DMT) and Banisteriopsis caapi contains much of β-carboline alkaloids (harmine, harmaline and tetrahydroharmine), which are monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s. It is believed that the main action of β-carbolines in Ayahuasca is to prevent the metabolization
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of DMT in the digestive tract and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, so it can cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, whereas the direct effect of β-carbolines on the central nervous system is minimal. The poison of the toad toad, Bufo alvarius, was also used as a hallucinogen. One of the most common hallucinogenic drugs, lysergic acid diethylamide (LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
), is a semi-synthetic tryptamine.