Indole Alkaloid
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Indole alkaloids are a class of alkaloids containing a structural moiety of
indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...
; many indole alkaloids also include
isoprene Isoprene, or 2-methyl-1,3-butadiene, is a common volatile organic compound with the formula CH2=C(CH3)−CH=CH2. In its pure form it is a colorless volatile liquid. It is produced by many plants and animals (including humans) and its polymers ar ...
groups and are thus called terpene indole or secologanin tryptamine alkaloids. 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 acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
is the
biochemical Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, ...
precursor of indole alkaloids.


History

The action of some indole alkaloids has been known for ages.
Aztec The Aztecs ( ) were a Mesoamerican civilization that flourished in central Mexico in the Post-Classic stage, post-classic period from 1300 to 1521. The Aztec people included different Indigenous peoples of Mexico, ethnic groups of central ...
s used the psilocybin mushrooms which contain alkaloids
psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...
and
psilocin Psilocin, also known as 4-hydroxy-''N'',''N''-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocy ...
. The flowering plant ''
Rauvolfia serpentina ''Rauvolfia serpentina'', the Indian snakeroot, devil pepper, serpentine wood, Sarpagandha (as known locally) or Chandrika, is a species of flower in the milkweed family Apocynaceae. It is native to the Indian subcontinent and East Asia (from Ind ...
'' which contains
reserpine Reserpine is a drug that is used for the treatment of hypertension, high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diur ...
was a common medicine in
India India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...
around 1000 BC. Africans used the roots of the
perennial In horticulture, the term perennial ('' per-'' + '' -ennial'', "through the year") is used to differentiate a plant from shorter-lived annuals and biennials. It has thus been defined as a plant that lives more than 2 years. The term is also ...
rainforest Rainforests are forests characterized by a closed and continuous tree Canopy (biology), canopy, moisture-dependent vegetation, the presence of epiphytes and lianas and the absence of wildfire. Rainforests can be generally classified as tropi ...
shrub Iboga, which contain ibogaine, as a stimulant. An infusion of Calabar bean seeds was given to people accused of crime in
Nigeria Nigeria, officially the Federal Republic of Nigeria, is a country in West Africa. It is situated between the Sahel to the north and the Gulf of Guinea in the Atlantic Ocean to the south. It covers an area of . With Demographics of 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 Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...
of the heart and lungs. Consumption of rye and related
cereal A cereal is a grass cultivated for its edible grain. Cereals are the world's largest crops, and are therefore staple foods. They include rice, wheat, rye, oats, barley, millet, and maize ( Corn). Edible grains from other plant families, ...
s contaminated with the
fungus A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...
'' 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 Strychnine (, , American English, US chiefly ) is a highly toxicity, toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, ...
, was isolated by Pierre Joseph Pelletier and Joseph Bienaimé Caventou in 1818 from the plants of the genus ''
Strychnos ''Strychnos'' is a genus of flowering plants, belonging to the family Loganiaceae (sometimes Strychnaceae). The genus includes about 200 accepted species of trees and lianas. The genus is widely distributed around the world's tropics and is n ...
''. The correct structural formula of strychnine was determined only in 1947, although the presence of the indole nucleus in the structure of strychnine was established somewhat earlier.Hesse, p. 316. Indole itself was first obtained by
Adolf von Baeyer Johann Friedrich Wilhelm Adolf von Baeyer (; 31 October 1835 – 20 August 1917) was a German chemist who synthesised indigo dye, indigo and developed a Von Baeyer nomenclature, nomenclature for cyclic compounds (that was subsequently extended a ...
in 1866 while decomposing
Indigo InterGlobe Aviation Limited (d/b/a IndiGo), is an India, Indian airline headquartered in Gurgaon, Haryana, India. It is the largest List of airlines of India, airline in India by passengers carried and fleet size, with a 64.1% domestic market ...
.


Classification

Indole alkaloids are distinguished depending on their biosynthesis. The two types of indole alkaloids are isoprenoids and non-isoprenoids. The latter include
terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic compound, organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeabl ...
structural elements, synthesized by living organisms from dimethylallyl pyrophosphate (DMAPP) and/or isopentenyl pyrophosphate (IPP): *Non-isoprenoid: **Simple derivatives of
indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...
**Simple derivatives of β-carboline **Pyrroloindole alkaloids ** Indole-3-carbinol **
Indole-3-acetic acid Indole-3-acetic acid (IAA, 3-IAA) is the most common naturally occurring plant hormone of the auxin class. It is the best known of the auxins, and has been the subject of extensive studies by plant physiologists. IAA is a derivative of indole, con ...
**
Tryptamines Substituted tryptamines, or simply tryptamines, also known as serotonin analogues (i.e., 5-hydroxytryptamine analogues), are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all trypt ...
**Carbazoles *Isoprenoid: ** hemiterpenoids: ergot alkaloids ** monoterpenoids. **Strictosidine **Catharanthine **Yohimbine **Vinca **Strychnine **
Ellipticine Ellipticine is a tetracyclic alkaloid first extracted from the tree species ''Ochrosia elliptica'' and ''Rauvolfia sandwicensis'' which inhibits the enzyme topoisomerase II via intercalation (biochemistry), intercalative binding to DNA. ...
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.


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 A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic b ...
tryptamine and 5-hydroxytryptamine (
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
). Although their assignment to the alkaloid is not universally accepted, they are both found in plants and animals.Dewick, p. 347 The tryptamine skeleton is part of the vast majority of indole alkaloids.Dewick, p. 350. For example, ''N'',''N''-
dimethyltryptamine Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a Psychedelic drug, serotonergic hallucinogen and Investigational New Drug, investigational drug of the substituted tryptamine, tryptamine family tha ...
(DMT),
psilocin Psilocin, also known as 4-hydroxy-''N'',''N''-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocy ...
and its phosphorylated
psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...
are the simplest derivatives of tryptamine. Some simple indole alkaloids do not contain tryptamine, such as gramine and glycozoline (the latter is a derivative of carbazole). Camalexin is a simple indole alkaloid produced by the plant ''Arabidopsis thaliana'', often used as a model for plant biology.


Simple derivatives of β-carboline

The prevalence of β-carboline 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 1838 by Göbel and harmine in 1848 by Fritzche.


Pyrolo-indole alkaloids

Pyrolo-indole alkaloids form a relatively small group of tryptamine derivatives. They are produced by
methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...
of indole nucleus at position 3 and the subsequent
nucleophilic addition In organic chemistry, a nucleophilic addition (AN) reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic addit ...
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.


Isoprenoid indole alkaloids

Isoprenoid indole alkaloids include residues of tryptophan or tryptamine and isoprenoid building blocks derived from the dimethylallyl pyrophosphate and isopentenyl pyrophosphate.


Ergot alkaloids

Ergot alkaloids are a class of hemiterpenoid indole alkaloids related to lysergic acid, which, in turn, is formed in a multistage reactions involving
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
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:Orekhov, p. 627. *Water-soluble aminoalcohol derivatives, such as ergometrine and its
isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...
ergometrinine *Water-insoluble
polypeptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...
derivatives: ** Ergotamine group, including ergotamine, ergosine and their isomers ** Ergoxine groups, including ergostine, ergoptine, ergonine and their isomers ** Ergotoxine group, including ergocristine, α- ergocryptine, 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.


Monoterpenoid Indoles Alkaloids or Secologanin Tryptamine Alkaloids

Most monoterpenoid alkaloids include a 9 or 10 carbon fragment (bold in image) (originating from the
secologanin Secologanin is a secoiridoid monoterpene synthesized from geranyl pyrophosphate in the mevalonate pathway. Secologanin then proceeds with dopamine or tryptamine to form ipecac and terpene indole alkaloids, respectively. Biosynthesis Secologa ...
), and the configuration allows grouping to ''Corynanthe'', ''Iboga'' and ''Aspidosperma'' classes. The monoterpenoid part of their carbon skeletons are illustrated below on the example of alkaloids ajmalicine and catharanthine. 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 alkaloids'' and ''Aspidosperma'' alkaloids. Some representative monoterpenoid indole alkaloids:Dewick, pp. 350–359 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.


Bisindole alkaloids

Dimers of strictosidine derivatives, loosely called bisindoles but more complicated than that. More than 200 of dimeric indole alkaloids are known. They are produced in living organisms through dimerization of monomeric indole bases, in the following reactions: * Mannich reaction (voacamine) * Michael reaction (villalstonine) *
Condensation Condensation is the change of the state of matter from the gas phase into the liquid phase, and is the reverse of vaporization. The word most often refers to the water cycle. It can also be defined as the change in the state of water vapor ...
of
aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
s with
amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
s ( toxiferine, calebassine) *Oxidative coupling of tryptamines (calicantine); *Splitting of the functional group of one of the monomers ( vinblastine,
vincristine Vincristine, also known as leurocristine and sold under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin lym ...
). 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 is an individual chemical specimen - a heterocyclic aromatic organic compound - as well as the name of a family of many thousands of natural plant alkaloids, any one of which might be referred to as "an isoquinoline". It is a struc ...
fragments.


Distribution in nature

The plants that are rich in non-isoprenoid indole alkaloids include '' harmal'' (''Peganum harmala''), which contains harmane, harmine and harmaline, and Calabar bean (''Physostigma venenosum'') containing physostigmine.Waksmundzka, pp. 625–626 Some members of the family
Convolvulaceae Convolvulaceae (), commonly called the bindweed, bindweeds or morning glory, morning glories, is a Family (biology), family of about 60 genera and more than 1,650 species. These species are primarily herbaceous vines, but also include trees, sh ...
, in particular '' Ipomoea violacea'' and '' Turbina corymbosa'', contain ergolines and lysergamides. Despite the considerable structural diversity, most of monoterpenoid indole alkaloids is localized in three families of
dicotyledon The dicotyledons, also known as dicots (or, more rarely, dicotyls), are one of the two groups into which all the flowering plants (angiosperms) were formerly divided. The name refers to one of the typical characteristics of the group: namely, ...
plants:
Apocynaceae Apocynaceae (, from '' Apocynum'', Greek for "dog-away") is a family of flowering plants that includes trees, shrubs, herbs, stem succulents, and vines, commonly known as the dogbane family, because some taxa were used as dog poison. Notable mem ...
(genera '' Alstonia'', '' Aspidosperma'', ''
Rauvolfia ''Rauvolfia'' (sometimes spelled ''Rauwolfia'') is a genus of evergreen trees and shrubs, commonly known as devil peppers, in the family Apocynaceae. The genus is named to honor Leonhard Rauwolf. The genus can mainly be found in Tropics, trop ...
'' and '' Catharanthus''),
Rubiaceae Rubiaceae () is a family (biology), family of flowering plants, commonly known as the coffee, madder, or bedstraw family. It consists of terrestrial trees, shrubs, lianas, or herbs that are recognizable by simple, opposite leaves with Petiole ( ...
('' Corynanthe'') and Loganiaceae (''
Strychnos ''Strychnos'' is a genus of flowering plants, belonging to the family Loganiaceae (sometimes Strychnaceae). The genus includes about 200 accepted species of trees and lianas. The genus is widely distributed around the world's tropics and is n ...
''). Indole alkaloids are also present in fungi. For example, psilocybin mushrooms contains derivatives of tryptamine and ''
Claviceps Ergot ( ) or ergot fungi refers to a group of fungi of the genus ''Claviceps''. The most prominent member of this group is '' Claviceps purpurea'' ("rye ergot fungus"). This fungus grows on rye and related plants, and produces alkaloids that c ...
'' contains derivatives of lysergic acid. The skin of many toad species of the genus '' Bufo'' contains a derivative of tryptamine, bufotenin, and the skin and venom of the species ''Bufo alvarius'' ( Colorado River toad) contains 5-MeO-DMT.
Serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
, which is an important
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
in mammals, can also be attributed to simple indole alkaloids. File:Peganum harmala1.jpg, '' Peganum harmala'' contains monoamine oxidase-inhibiting β-carboline alkaloids File:Physostigma venenosum - Köhler–s Medizinal-Pflanzen-237.jpg, '' Physostigma venenosum'' "Calabar bean", source of physostigmine (coloured plate from
Köhler's Medicinal Plants ''Köhler's Medicinal Plants'' (or, ''Köhler's Medizinal-Pflanzen'') is a German herbal written principally by Hermann Adolph Köhler (1834–1879, physician and chemist), and edited after his death by Gustav Pabst. The work was first publishe ...
) File:Urbana Illinois park 20070929 img 2141.jpg, '' Ipomoea violacea'' contains ergolines File:Strychnos toxifera - Köhler–s Medizinal-Pflanzen-267.jpg, '' Strychnos toxifera'', source of the paralysant alkaloid toxiferine (coloured plate from Köhler's Medicinal Plants) File:Strychnos nux-vomica - Köhler–s Medizinal-Pflanzen-266.jpg, ''
Strychnos nux-vomica ''Strychnos nux-vomica'', the strychnine tree, also known as nux vomica, poison fruit, semen strychnos, and quaker buttons, is a deciduous tree native to India and to southeast Asia. It is a medium-sized tree in the family Loganiaceae that grows ...
'', principal source of the
convulsant A convulsant is a drug which induces convulsions or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to poor therapeutic indices. Most convulsant ...
alkaloid
strychnine Strychnine (, , American English, US chiefly ) is a highly toxicity, toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, ...
(coloured plate from Köhler's Medicinal Plants) File:Tabernanthe iboga MS 4098.jpg, '' Tabernanthe iboga'', principal source of the
entheogen Entheogens are psychoactive substances used in spiritual and religious contexts to induce altered states of consciousness. Hallucinogens such as the psilocybin found in so-called "magic" mushrooms have been used in sacred contexts since ancie ...
Ibogaine File:Alstonia macrophylla (Batino) in Hyderabad W2 IMG 9005.jpg , '' Alstonia macrophylla'' contains ''Corynanthe'' alkaloids File:Rauwolfia serpentina(Flower).jpg, ''
Rauvolfia serpentina ''Rauvolfia serpentina'', the Indian snakeroot, devil pepper, serpentine wood, Sarpagandha (as known locally) or Chandrika, is a species of flower in the milkweed family Apocynaceae. It is native to the Indian subcontinent and East Asia (from Ind ...
'' contains ''Corynanthe'' alkaloids File:Starr 061223-2741 Catharanthus roseus.jpg, '' Catharanthus roseus'' contains monoterpenoid indole alkaloids File:Crape Jasmine.jpg, ''
Tabernaemontana divaricata ''Tabernaemontana divaricata'', commonly called pinwheel flower, crape jasmine, East India rosebay, and Nero's crown, is an evergreen shrub or small tree native to South Asia, Southeast Asia and China. In zones where it is not hardy it is grown a ...
'' contains indole alkaloids including
catharanthine Catharanthine is a terpene indole alkaloid produced by the medicinal plant '' Catharanthus roseus'' and '' Tabernaemontana divaricata''. Catharanthine is derived from strictosidine, but the exact mechanism by which this happens is currently unkn ...
,
conophylline Conophylline is a autophagy inducing vinca alkaloid found in plants of the genus ''Tabernaemontana''. Among the many functional groups in this molecule is an epoxide: the compound where that ring is replaced with a double bond is called conophylli ...
,
ibogamine Ibogamine is an anti-convulsant, anti-addictive, CNS stimulant alkaloid found in '' Tabernanthe iboga'' and Crepe Jasmine ('' Tabernaemontana divaricata''). Basic research related to how addiction affects the brain has used this chemical. Iboga ...
, tabersonine and
voacristine Voacristine is a indole alkaloid occurring in '' Voacanga'' and '' Tabernaemontana'' genus. It is also an iboga type alkaloid. Chemistry Its structure is almost similar to voacangine, an alkaloid used in semi-synthesis of ibogaine. Compared ...
File:Pcubmazatapec.jpg , '' Psilocybe cubensis'' contains
psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...
and
psilocin Psilocin, also known as 4-hydroxy-''N'',''N''-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocy ...
File:Claviceps purpurea.JPG, Ergot contains ergolines File:2009-03-13Bufo alvarius071.jpg, The Colorado River toad (''Bufo alvarius'') secretes bufotenin and 5-MeO-DMT from its
parotoid gland The parotoid gland (alternatively, paratoid gland) is an external skin gland on the back, neck, and shoulder of some frogs (especially toads), and salamanders. It can secrete a number of milky alkaloid substances (depending on the species) known ...
s


Biosynthesis

Biogenetic precursor of all indole alkaloids is the amino acid
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...
. For most of them, the first synthesis step is decarboxylation of tryptophan to form tryptamine.
Dimethyltryptamine Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a Psychedelic drug, serotonergic hallucinogen and Investigational New Drug, investigational drug of the substituted tryptamine, tryptamine family tha ...
(DMT) is formed from tryptamine by
methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...
with the participation of
coenzyme A cofactor is a non-protein chemical compound or Metal ions in aqueous solution, metallic ion that is required for an enzyme's role as a catalysis, catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can ...
of S-adenosyl methionine (SAM).
Psilocin Psilocin, also known as 4-hydroxy-''N'',''N''-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocy ...
is produced by spontaneous dephosphorylation of
psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...
. 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 In organic chemistry, a Schiff base (named after Hugo Schiff) is a compound with the general structure ( = alkyl or aryl, but not hydrogen). They can be considered a sub-class of imines, being either secondary ketimines or secondary aldim ...
from tryptamine and
aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
(or keto acid) and subsequent intramolecular Mannich reaction, where the C(2) carbon atom of indole serves as a
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
. Then, the
aromaticity In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugation alone. The e ...
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 (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an metabolic intermediate, intermediate in several m ...
acts as the keto acid. In the synthesis of monoterpenoid indole alkaloids,
secologanin Secologanin is a secoiridoid monoterpene synthesized from geranyl pyrophosphate in the mevalonate pathway. Secologanin then proceeds with dopamine or tryptamine to form ipecac and terpene indole alkaloids, respectively. Biosynthesis Secologa ...
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-dimethylallyl-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 Strictosidine is a natural chemical compound and is classified as a glucoalkaloid and a vinca alkaloid. It is formed by the Pictet–Spengler condensation reaction of tryptamine with secologanin, catalyzed by the enzyme strictosidine synthase. ...
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, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a Cofactor (biochemistry), cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid synt ...
(NADPH). In the biosynthesis of other alkaloids, 4,21-dehydrogeissoschizine first converts into preakuammicine (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, also known as leurocristine and sold under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin lym ...
are produced in the reaction involving catharanthine (alkaloid of type ''Iboga'') and vindolin (type ''Aspidosperma'').


Physiological activity

Indole alkaloids act on the central and
peripheral A peripheral device, or simply peripheral, is an auxiliary hardware device that a computer uses to transfer information externally. A peripheral is a hardware component that is accessible to and controlled by a computer but is not a core compo ...
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 receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the Central nervous system, central and peripheral nervous systems ...
s. The main effect of the
serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...
s such as LSD, DMT, and
psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...
is related to them being
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s of the 5-HT2A receptors. In contrast, gramine is an antagonist of the 5-HT2A receptor. Ergolines, such as 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 An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of α-adrenergic and 5-HT2 receptors, and thus narrows blood vessels and stimulates constriction of the
uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
. 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 semi-synthetic psychedelic ergoline, is an agonist of 5-HT2A, 5-HT1A and to a lesser extent D2 receptors and has a powerful psychedelic 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.Dewick, p. 353 Yohimbine is more selective to α2 adrenoceptor; by blocking presynaptic α2-adrenoceptors, it increases the release of
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
thereby raising the blood pressure. Yohimbine was used for the treatment of
erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...
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 Reserpine is a drug that is used for the treatment of hypertension, high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diur ...
reduces concentration of monoamines in presynaptic and synaptic neurons, thereby inducing antihypertensive and antipsychotic effects. Some indole alkaloids interact with other types of receptors. 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 Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level an ...
.


Applications

Plants and fungi that contain indole alkaloids have a long history of use in
traditional medicine Traditional medicine (also known as indigenous medicine or folk medicine) refers to the knowledge, skills, and practices rooted in the cultural beliefs of various societies, especially Indigenous groups, used for maintaining health and treatin ...
. ''
Rauvolfia serpentina ''Rauvolfia serpentina'', the Indian snakeroot, devil pepper, serpentine wood, Sarpagandha (as known locally) or Chandrika, is a species of flower in the milkweed family Apocynaceae. It is native to the Indian subcontinent and East Asia (from Ind ...
'', which contains reserpine as the active substance, was used for over 3000 years in
India India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...
to treat snake bites and
insanity Insanity, madness, lunacy, and craziness are behaviors caused by certain abnormal mental or behavioral patterns. Insanity can manifest as violations of societal norms, including a person or persons becoming a danger to themselves or to other ...
. In medieval Europe, extracts of ergot were used in
medical abortion A medical abortion, also known as medication abortion or non-surgical abortion, occurs when drugs (medication) are used to bring about an abortion. Medical abortions are an alternative to surgical (also called procedural or instrumentation) a ...
. Later, the plants were joined by pure preparations of indole alkaloids. Reserpine was the second (after
chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...
)
antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
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 In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
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 Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...
,
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
( 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 Heroin, also known as diacetylmorphine and diamorphine among other names, is a morphinan opioid substance synthesized from the Opium, dried latex of the Papaver somniferum, opium poppy; it is mainly used as a recreational drug for its eupho ...
,
cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...
, and
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
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 psychedelic drug with dangerous implications of overdose. However, illegal network in
Europe Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west, the Mediterranean Sea to the south, and Asia to the east ...
and
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
provide ibogaine for treating drug addiction. Since ancient times, plants containing indole alkaloids have been used as
psychedelic drug Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluc ...
s. The
Aztec The Aztecs ( ) were a Mesoamerican civilization that flourished in central Mexico in the Post-Classic stage, post-classic period from 1300 to 1521. The Aztec people included different Indigenous peoples of Mexico, ethnic groups of central ...
s used and the Mazatec people continue to use psilocybin mushrooms and the psychoactive seeds of
morning glory Morning glory (also written as morning-glory) is the common name for over 1,000 species of flowering plants in the family Convolvulaceae, whose taxonomy and systematics remain in flux. These species are distributed across numerous genus, gene ...
species like ''
Ipomoea tricolor ''Ipomoea tricolor'', the Mexican morning glory or just morning glory, is a species of flowering plant in the family (biology), family Convolvulaceae, native plant, native to the tropics of the Americas, and widely cultivated and naturalisation ...
''. Amazonian tribes use the psychedelic infusion,
ayahuasca AyahuascaPronounced as in the UK and in the US. Also occasionally known in English as ''ayaguasca'' (Spanish-derived), ''aioasca'' (Brazilian Portuguese-derived), or as ''yagé'', pronounced or . Etymologically, all forms but ''yagé'' descen ...
, made from ''
Psychotria viridis ''Psychotria viridis'', also known as ''chacruna'', ''chacrona'', or ''chaqruy'' in the Quechua languages, is a perennial, shrubby flowering plant in the coffee family Rubiaceae. It is a close relative of ''Psychotria carthagenensis'' (a.k.a. ''s ...
'' and ''
Banisteriopsis caapi ''Banisteriopsis caapi'', also known as, caapi, soul vine, yagé (yage), or ayahuasca (the latter of which also refers to the psychedelic decoction made with the vine and a plant source of dimethyltryptamine) is a South American liana of the fam ...
''.Christina Pratt (2007
An Encyclopedia of Shamanism Volume 1
The Rosen Publishing Group, p. 310
''Psychotria viridis'' contains the psychedelic drug DMT, while ''Banisteriopsis caapi'' contains
harmala alkaloid Harmala alkaloids are several alkaloids that act as monoamine oxidase inhibitors (MAOIs). These alkaloids are found in the seeds of ''Peganum harmala'' (also known as harmal or Syrian rue), as well as ''Banisteriopsis caapi'' (ayahuasca), leave ...
s, which act as
monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...
s. It is believed that the main function of the harmala alkaloids in ayahuasca is to prevent the metabolization of DMT in the
digestive tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
and
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, so it can cross the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
, whereas the direct effect of harmala alkaloids on the central nervous system is minimal. The venom of the Colorado River toad, ''Bufo alvarius'', may have used as a psychedelic drug, its active constituents being 5-MeO-DMT and bufotenin. One of the most common recreational
psychedelic drug Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluc ...
s, LSD, is a semi-synthetic ergoline (which contains the indole moiety).Dewick, p. 376


References


Bibliography

* * * * *{{cite book, author1=Waksmundzka-Hajnos, Monika , author2=Sherma, Joseph , author3=Kowalska, Teresa , title = Thin layer chromatography in phytochemistry, url= https://books.google.com/books?id=fBCDK_Tgh10C, year = 2008, publisher = CRC Press, isbn = 978-1-4200-4677-9