Indole alkaloids are a class of alkaloids containing a structural moiety of

indole Indole is an aromatic heterocyclic organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other c ...

; many indole alkaloids also include isoprene 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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha 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 aromatic ...

is the biochemical precursor of indole alkaloids.

History

The action of some indole alkaloids has been known for ages.

Aztec The Aztecs () were a Mesoamerican culture that flourished in central Mexico in the post-classic period from 1300 to 1521. The Aztec people included different ethnic groups of central Mexico, particularly those groups who spoke the Nahuatl ...

s used the

psilocybin mushroom Psilocybin mushrooms, commonly known as magic mushrooms, are a polyphyletic informal group of fungi that contain psilocybin which turns into psilocin upon ingestion. Biological genera containing psilocybin mushrooms include ''Psilocybe'', '' ...

s which contain alkaloids

psilocybin Psilocybin ( , ) is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of the genus ''Psilocybe'', such as '' P. azurescens'', '' P. semilanceata'', and '' P.&nbs ...

and

psilocin Psilocin (also known as 4-HO-DMT, 4-hydroxy DMT, psilocine, psilocyn, or psilotsin) is a substituted tryptamine alkaloid and a serotonergic psychedelic substance. It is present in most psychedelic mushrooms together with its phosphorylated cou ...

. The flowering plant '' Rauvolfia serpentina'' which contains reserpine was a common medicine in

India India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...

around 1000 BC. Africans used the roots of the

perennial A perennial plant or simply perennial is a plant that lives more than two years. The term ('' per-'' + '' -ennial'', "through the years") is often used to differentiate a plant from shorter-lived annuals and biennials. The term is also wid ...

rainforest shrub Iboga, which contain

ibogaine Ibogaine is a naturally occurring psychoactive substance found in plants in the family Apocynaceae such as '' Tabernanthe iboga'', '' Voacanga africana'', and '' Tabernaemontana undulata''. It is a psychedelic with dissociative properties. Pre ...

, as a stimulant. An infusion of

Calabar bean ''Physostigma venenosum'', the Calabar bean or ordeal bean, is a leguminous plant, Endemic to tropical Africa, with a seed poisonous to humans. It derives the first part of its scientific name from a curious beak-like appendage at the end of th ...

seeds was given to people accused of crime in

Nigeria Nigeria ( ), , ig, Naìjíríyà, yo, Nàìjíríà, pcm, Naijá , ff, Naajeeriya, kcg, Naijeriya officially the Federal Republic of Nigeria, is a country in West Africa. It is situated between the Sahel to the north and the Gulf o ...

: its rejection by stomach was regarded as a sign of innocence, otherwise, the person was killed via the action of

physostigmine Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean a ...

, which is present in the plant and which causes paralysis of the heart and lungs. Consumption of rye and related cereals contaminated with the

fungus A fungus ( : fungi or funguses) is any member of the 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, separately from t ...

Claviceps purpurea ''Claviceps purpurea'' is an ergot fungus that grows on the ears of rye and related cereal and forage plants. Consumption of grains or seeds contaminated with the survival structure of this fungus, the ergot sclerotium, can cause ergotism in h ...

'' 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 Ergotamine, sold under the brand names Cafergot (with caffeine) and Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It possesses structural sim ...

, one of the main active ingredients of ergot, was isolated in 1918. The first indole alkaloid, strychnine, was isolated by

Pierre Joseph Pelletier Pierre-Joseph Pelletier (, , ; 22 March 1788 – 19 July 1842) was a French chemist and pharmacist who did notable research on vegetable alkaloids, and was the co-discoverer with Joseph Bienaimé Caventou of quinine, caffeine, and strychnine ...

and

Joseph Bienaimé Caventou Joseph Bienaimé Caventou (30 June 1795 – 5 May 1877) was a French pharmacist. He was a professor at the École de Pharmacie (School of Pharmacy) in Paris. He collaborated with Pierre-Joseph Pelletier in a Parisian laboratory located behind an ...

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 100 accepted species of trees and lianas, and more than 200 that are as yet unresolved. The genus is widely di ...

''. 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 and developed a nomenclature for cyclic compounds (that was subsequently extended and adopted as part of the IUPAC org ...

in 1866 while decomposing

Indigo Indigo is a deep color close to the color wheel blue (a primary color in the RGB color space), as well as to some variants of ultramarine, based on the ancient dye of the same name. The word "indigo" comes from the Latin word ''indicum'', m ...

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 chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes" ...

structural elements, synthesized by living organisms from

dimethylallyl pyrophosphate Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynt ...

(DMAPP) and/or

isopentenyl pyrophosphate Isopentenyl pyrophosphate (IPP, isopentenyl diphosphate, or IDP) is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway (commonly called the mevalonate pathway) and in the ''non-mevalonate'' MEP pathway of i ...

(IPP): *Non-isoprenoid: **Simple derivatives of

**Simple derivatives of

β-carboline β-Carboline (9''H''-Pyridine, pyrido ,4-''b''ndole) represents the basic chemical structure for more than one hundred alkaloids and synthetic compounds. The effects of these substances depend on their respective substituent. Natural β-carbo ...

**Pyrroloindole alkaloids **

Indole-3-carbinol Indole-3-carbinol ( C9 H9 N O), sometimes referred to as I3C, is produced by the breakdown of the glucosinolate glucobrassicin, which can be found at relatively high levels in cruciferous vegetables such as broccoli, cabbage, cauliflower, brusse ...

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 serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino (NH2) group via an ethy ...

**Carbazoles *Isoprenoid: ** hemiterpenoids: ergot alkaloids **

monoterpenoids Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings (monocyclic and bicyclic). Modified terpenes, such as those containing oxygen funct ...

. **Strictosidine **Catharanthine **Yohimbine **Vinca **Strychnine ** Ellipticine There are also purely structural classifications based on the presence of

carbazole Carbazole is an aromatic heterocyclic organic compound. It has a tricyclic structure, consisting of two six-membered benzene rings fused on either side of a five-membered nitrogen-containing ring. The compound's structure is based on the indole str ...

, 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 ...

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. The chemical structure is defined by an indole ─ a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the f ...

and 5-hydroxytryptamine ( serotonin). 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 ''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as a ...

(DMT),

and its

phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

are the simplest derivatives of tryptamine. Some simple indole alkaloids do not contain tryptamine, such as

gramine Gramine (also called donaxine) 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 Gramine has been found in the giant reed, ...

and glycozoline (the latter is a derivative of

Camalexin Camalexin (3-thiazol-2-yl-indole) is a simple indole alkaloid found in the plant ''Arabidopsis thaliana'' and other crucifers. The secondary metabolite functions as a phytoalexin to deter bacterial and fungal pathogens. Structure The base struc ...

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

alkaloids is associated with the ease of forming the β-carboline core from tryptamine in the intramolecular

Mannich reaction In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of an acidic proton next to a carbonyl () functional group by formaldehyde () and a primary or secondary amine () or ammonia (). ...

. Simple (non-isoprenoid) β-carboline derivatives include

harmine Harmine is a beta-carboline and a harmala alkaloid. It occurs in a number of different plants, most notably the Syrian rue and ''Banisteriopsis caapi''. Harmine reversibly inhibits monoamine oxidase A (MAO-A), an enzyme which breaks down monoamin ...

harmaline Harmaline is a fluorescent indole alkaloid from the group of harmala alkaloids and beta-carbolines. It is the partly hydrogenated form of harmine. Occurrence in nature Various plants contain harmaline including ''Peganum harmala'' (Syrian rue) ...

harmane Harmane (harman) is a heterocyclic amine found in a variety of foods including coffee, sauces, and cooked meat. It is also present in tobacco smoke. Chemistry Harmane is a methylated derivative In mathematics, the derivative of a functi ...

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 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

, 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

and

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

and DMAPP. Many ergot alkaloids are

amides In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

of lysergic acid. The simplest such amide is

ergine Ergine, also known as d-lysergic acid amide (LSA) and d-lysergamide, is an ergoline alkaloid that occurs in various species of vines of the Convolvulaceae and some species of fungi. The psychedelic properties in the seeds of ololiuhqui, Hawai ...

, and more complex can be distinguished into the following groups:Orekhov, p. 627. *Water-soluble

aminoalcohol In organic chemistry, alkanolamines are organic compounds that contain both hydroxyl () and amino (, , and ) functional groups on an alkane backbone. The term alkanolamine is a broad class term that is sometimes used as a subclassification. Meth ...

derivatives, such as

ergometrine Ergometrine, also known as ergonovine and sold under the brand names Ergotrate, Ergostat, and Syntometrine among others, is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used ei ...

and its isomer ergometrinine *Water-insoluble polypeptide derivatives: **

Ergotamine Ergotamine, sold under the brand names Cafergot (with caffeine) and Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It possesses structural sim ...

group, including ergotamine, ergosine and their isomers ** Ergoxine groups, including ergostine, ergoptine, ergonine and their isomers ** Ergotoxine group, including

ergocristine Ergocristine is an ergopeptine and one of the ergot alkaloids. As of February 24, 2010 ergocristine has been federally scheduled. Because of the existing Controlled Substance Act regulatory controls on the LSD precursors lysergic acid, lysergi ...

, 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,

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 Secologanin ...

), 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'' 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: *

(voacamine) *

Michael reaction In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...

(villalstonine) * Condensation of

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

s with

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen Hydrogen is the chemical element wi ...

s (

toxiferine Toxiferine (C-toxiferine I) is a curare toxin. It is a bisindole alkaloid derived from ''Strychnos toxifera'' and a nicotinic acetylcholine receptor antagonist. This alkaloid is the main toxic component of Calabash curare, and one of the most t ...

, calebassine) *Oxidative coupling of tryptamines (calicantine); *Splitting of the functional group of one of the monomers (

vinblastine Vinblastine (VBL), sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. This includes Hodgkin's lymphoma, non-small cell lung cancer, bladder ca ...

vincristine Vincristine, also known as leurocristine and marketed 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's ...

). 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 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 isoqu ...

fragments.

Distribution in nature

The plants that are rich in non-isoprenoid indole alkaloids include ''

harmal ''Peganum harmala'', commonly called wild rue, Syrian rue, African rue, esfand or espand,Mahmoud OmidsalaEsfand: a common weed found in Persia, Central Asia, and the adjacent areasEncyclopedia Iranica Vol. VIII, Fasc. 6, pp. 583–584. Originall ...

'' (''Peganum harmala''), which contains harmane, harmine and harmaline, and

(''Physostigma venenosum'') containing

.Waksmundzka, pp. 625–626 Some members of the family

Convolvulaceae Convolvulaceae (), commonly called the bindweeds or morning glories, is a family of about 60 genera and more than 1,650 species. These species are primarily herbaceous vines, but also include trees, shrubs and herbs. The tubers of several spe ...

, in particular ''

Ipomoea violacea ''Ipomoea violacea'' is a perennial species of ''Ipomoea'' that occurs throughout the world with the exception of the European continent. It is most commonly called beach moonflower or sea moonflower as the flowers open at night. Description The ...

'' and '' Turbina corymbosa'', contain

ergoline Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of thes ...

s and

lysergamides Amides of lysergic acid are collectively known as lysergamides, and include a number of compounds with potent agonist and/or antagonist activity at various serotonin and dopamine Receptor (biochemistry), receptors. See also * Ergoline * Brom ...

. Despite the considerable structural diversity, most of monoterpenoid indole alkaloids is localized in three families of dicotyledon 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 Members of ...

(genera '' Alstonia'', '' Aspidosperma'', '' Rauvolfia'' and ''

Catharanthus ''Catharanthus'' is a genus of flowering plants in the family Apocynaceae. Like the genus ''Vinca'', they are known commonly as periwinkles. There are eight known species. Seven are endemic to Madagascar,Rubiaceae The Rubiaceae are a 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 interpetiolar stipules a ...

('' Corynanthe'') and

Loganiaceae The Loganiaceae are a family of flowering plants classified in order Gentianales. The family includes up to 13 genera, distributed around the world's tropics. There are not any great morphological characteristics to distinguish these taxa from ot ...

(''

''). Indole alkaloids are also present in fungi. For example,

s contains derivatives of tryptamine and '' Claviceps'' contains derivatives of lysergic acid. The skin of many toad species of the genus ''

Bufo ''Bufo'' is a genus of true toads in the amphibian family Bufonidae. As traditionally defined, it was a wastebasket genus containing a large number of toads from much of the world, but following taxonomic reviews most of these have been moved t ...

'' contains a derivative of tryptamine,

bufotenin Bufotenin (5-HO-DMT, bufotenine) is a tryptamine derivative - more specifically, a DMT derivative - related to the neurotransmitter serotonin. It is an alkaloid found in some species of toads (especially the skin), mushrooms and plants. ...

, and the skin and venom of the species ''Bufo alvarius'' (

Colorado River toad The Colorado River toad (''Incilius alvarius''), formerly known as the Sonoran Desert toad, is found in northern Mexico and the southwestern United States. It exudes toxins from glands within its skin that have psychoactive properties. Descript ...

) contains

5-MeO-DMT 5-MeO-DMT (5-methoxy-''N'',''N''-dimethyltryptamine) or O-methyl-bufotenin is a psychedelic of the tryptamine class. It is found in a wide variety of plant species, and also is secreted by the glands of at least one toad species, the Colorado R ...

. Serotonin, which is an important neurotransmitter in mammals, can also be attributed to simple indole alkaloids. File:Peganum harmala1.jpg, ''

Peganum harmala ''Peganum harmala'', commonly called wild rue, Syrian rue, African rue, esfand or espand,Mahmoud OmidsalaEsfand: a common weed found in Persia, Central Asia, and the adjacent areasEncyclopedia Iranica Vol. VIII, Fasc. 6, pp. 583–584. Originall ...

'' contains monoamine oxidase-inhibiting

alkaloids File:Physostigma venenosum - Köhler–s Medizinal-Pflanzen-237.jpg, '' Physostigma venenosum'' "Calabar bean", source of

(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, ''

'' contains

s File:Strychnos toxifera - Köhler–s Medizinal-Pflanzen-267.jpg, ''

Strychnos toxifera ''Strychnos toxifera'', called bush rope and devil doer, is a species of flowering plant in the genus ''Strychnos'', native to Costa Rica, Panama, Colombia, Ecuador, Venezuela, the Guianas, Brazil, Peru and Bolivia. It is the principal source of ...

'', source of the paralysant alkaloid

(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 grow ...

'', principal source of the

convulsant A convulsant is a drug which induces convulsions and/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 the risk of convulsions and consequent e ...

alkaloid strychnine (coloured plate from Köhler's Medicinal Plants) File:Tabernanthe iboga MS 4098.jpg, ''

Tabernanthe iboga ''Tabernanthe iboga'' (iboga) is an evergreen rainforest shrub native to Central Africa. A member of the Apocynaceae family indigenous to Gabon, the Democratic Republic of Congo, and the Republic of Congo, it is cultivated across Central Africa ...

'', principal source of the

entheogen Entheogens are psychoactive substances that induce alterations in perception, mood, consciousness, cognition, or behavior for the purposes of engendering spiritual development or otherwiseRätsch, Christian, ''The Encyclopedia of Psychoac ...

Ibogaine Ibogaine is a naturally occurring psychoactive substance found in plants in the family Apocynaceae such as '' Tabernanthe iboga'', '' Voacanga africana'', and '' Tabernaemontana undulata''. It is a psychedelic with dissociative properties. Pre ...

File:Alstonia macrophylla (Batino) in Hyderabad W2 IMG 9005.jpg , '' Alstonia macrophylla'' contains ''Corynanthe'' alkaloids File:Rauwolfia serpentina(Flower).jpg, '' Rauvolfia serpentina'' contains ''Corynanthe'' alkaloids File:Starr 061223-2741 Catharanthus roseus.jpg, ''

Catharanthus roseus ''Catharanthus roseus'', commonly known as bright eyes, Cape periwinkle, graveyard plant, Madagascar periwinkle, old maid, pink periwinkle, rose periwinkle, is a species of flowering plant in the family Apocynaceae. It is native and endemic to M ...

'' 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,

conophylline Conophylline is a autophagy inducing vinca alkaloid found in several species of ''Tabernaemontana'' including '' Ervatamia microphylla'' and ''Tabernaemontana divaricata''. Among its many functional groups is an epoxide: the compound where that rin ...

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. Ibogam ...

, 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 to ...

File:Pcubmazatapec.jpg , '' Psilocybe cubensis'' contains

and

File:Claviceps purpurea.JPG, Ergot contains ergolines File:2009-03-13Bufo alvarius071.jpg, The

(''Bufo alvarius'') secretes

and

from its

parotoid gland The parotoid gland (alternatively, paratoid gland) is an external skin gland on the back, neck, and shoulder of toads and some frogs and salamanders. It can secrete a number of milky alkaloid substances (depending on the species) known collectiv ...

Biosynthesis

Biogenetic precursor of all indole alkaloids is the amino acid

. For most of them, the first synthesis step is decarboxylation of tryptophan to form

Dimethyltryptamine ''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as a ...

(DMT) is formed from tryptamine by methylation with the participation of

coenzyme A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...

S-adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...

(SAM).

Psilocin Psilocin (also known as 4-HO-DMT, 4-hydroxy DMT, psilocine, psilocyn, or psilotsin) is a substituted tryptamine alkaloid and a serotonergic psychedelic substance. It is present in most psychedelic mushrooms together with its phosphorylated cou ...

is produced by spontaneous dephosphorylation of

. In the biosynthesis of serotonin, the intermediate product is not tryptamine but 5-hydroxytryptophan, which is in turn decarboxylated to form 5-hydroxytryptamine (serotonin). Serotonin biosynthesis

Biosynthesis of

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 aldimine ...

from tryptamine and

(or

keto acid In organic chemistry, keto acids or ketoacids (also called oxo acids or oxoacids) are organic compounds that contain a carboxylic acid group () and a ketone group ().Franz Dietrich Klingler, Wolfgang Ebertz "Oxocarboxylic Acids" in Ullmann's En ...

) and subsequent intramolecular

, where the C(2) carbon atom of indole serves as a nucleophile. Then, the

aromaticity In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

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,

plays the role of the aldehyde. Pirroloindole alkaloids are synthesized in living organisms in a similar way. Beta-carboline moiety biosynthesis

Biosynthesis of ergot alkaloids begins with the alkylation of tryptophan by

(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. Lysergic acid biosynthesis

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 used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...

(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

are produced in the reaction involving catharanthine (alkaloid of type ''Iboga'') and vindolin (type ''Aspidosperma''). Terpenoid indoles biosynthesis

Physiological activity

Tryptamine and phenethylamine moieties in lysergic acid molecule

Indole alkaloids act on the central 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 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory ne ...

s. The main effect of the

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science of ...

s such as

LSD Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...

, DMT, and

is related to them being agonists of the 5-HT_2A receptors. In contrast, gramine is an antagonist of the 5-HT_2A receptor.

Ergoline Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of thes ...

s, 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 Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...

(mostly type D₂). So

is a partial agonist of α-adrenergic and 5-HT₂ receptors, and thus

narrows A narrows or narrow (used interchangeably but usually in the plural form), is a restricted land or water passage. Most commonly a narrows is a strait, though it can also be a water gap. A narrows may form where a stream passes through a tilted ...

blood vessels and stimulates constriction of the

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

. Dihydroergotamine is more selective to α-adrenergic receptors and has a weaker effect on serotonin receptors.

Ergometrine Ergometrine, also known as ergonovine and sold under the brand names Ergotrate, Ergostat, and Syntometrine among others, is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used ei ...

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.

, a semi-synthetic psychedelic ergoline, is an agonist of 5-HT_2A, 5-HT_1A 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 Yohimbine (), also known as quebrachine, is an indole alkaloid derived from the bark of the African tree '' Pausinystalia johimbe''; also from the bark of the unrelated South American tree ''Aspidosperma quebracho-blanco''. Yohimbine is an α2 ...

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 chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...

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. Mitragynine is an agonist of the μ-

opioid receptor Opioid receptors are a group of inhibitory 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 ...

. Harmal alkaloids are antagonists to the GABA_A-receptor, and

– to

NMDA-receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA an ...

Physostigmine Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean a ...

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 and ...

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) comprises medical aspects of traditional knowledge that developed over generations within the folk beliefs of various societies, including indigenous peoples, before the ...

. '' Rauvolfia serpentina'', which contains reserpine as the active substance, was used for over 3000 years in

to treat snake bites and

insanity Insanity, madness, lunacy, and craziness are behaviors performed by certain abnormal mental or behavioral patterns. Insanity can be manifest as violations of societal norms, including a person or persons becoming a danger to themselves or t ...

. In medieval Europe, extracts of ergot were used in

medical abortion A medical abortion, also known as medication abortion, occurs when drugs (medication) are used to bring about an abortion. Medical abortions are an alternative to surgical abortions such as vacuum aspiration or dilation and curettage. Medical ...

. 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 di ...

)

antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...

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 Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests th ...

, 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 Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...

, Alzheimer's disease (

rivastigmine Rivastigmine (sold under the trade name Exelon among others) is a cholinesterase inhibitor used for the treatment of mild to moderate Alzheimer's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces t ...

) and myasthenia (

neostigmine Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of n ...

pyridostigmine Pyridostigmine is a medication used to treat myasthenia gravis and underactive bladder. It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is typically given by mouth ...

, distigmine). Ergot alkaloids

(ergobazin, ergonovine),

and their synthetic derivatives (

methylergometrine Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and in the treatment of migraine. It reportedly produ ...

) are applied against uterine bleeding, and bisindole alkaloids vinblastine and vincristine are antitumor agents. Animal studies have shown that

has a potential in treating heroin,

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

, and alcohol addictions, which is associated with the ibogaine antagonism to

s. 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 large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a subcontinent of Eurasia and it is located entirel ...

and

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

provide ibogaine for treating drug addiction. LSD match

Since ancient times, plants containing indole alkaloids have been used as psychedelic drugs. The

s used and the

Mazatec people The Mazatec are an indigenous people of Mexico who inhabit the Sierra Mazateca in the state of Oaxaca and some communities in the adjacent states of Puebla and Veracruz. Language family The Mazatecan languages are part of the Popolocan family wh ...

continue to use

s 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 current taxonomy and systematics are in flux. Morning glory species belong to many genera, some of ...

species like ''

Ipomoea tricolor ''Ipomoea tricolor'', the Mexican morning glory or just morning glory, is a species of flowering plant in the family Convolvulaceae, native to the New World tropics, and widely cultivated and naturalised elsewhere. It is an herbaceous annual or ...

''. 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'' desce ...

, 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. ...

'' and ''

Banisteriopsis caapi ''Banisteriopsis caapi'', also known as ayahuasca, caapi, soul vine, or yagé (yage), is a South American liana of the family Malpighiaceae. It is one half of ayahuasca, a decoction with a long history of its entheogenic (connecting to spirit) us ...

''.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 alkaloids, which act as monoamine oxidase inhibitors. It is believed that the main function of the harmala alkaloids in ayahuasca is to prevent the

metabolization Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

of DMT in the

digestive tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

and

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, so it can cross the blood–brain barrier, whereas the direct effect of harmala alkaloids on the central nervous system is minimal. The venom of the

, ''Bufo alvarius'', may have used as a psychedelic drug, its active constituents being

and

. One of the most common

recreational Recreation is an activity of leisure, leisure being discretionary time. The "need to do something for recreation" is an essential element of human biology and psychology. Recreational activities are often done for enjoyment, amusement, or pleasur ...

psychedelic drugs,

, is a semi-synthetic

(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