Indole alkaloid

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; 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.[1] Many of them possess significant physiological activity and some of them are used in
medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.[2]

Contents
History
Structural formula of indole
Classification
Non-isoprenoid indole alkaloids
Simple indole derivatives
Simple derivatives of β-carboline
Pyrolo-indole alkaloids
Isoprenoid indole alkaloids
Ergot alkaloids
Monoterpenoid Indoles Alkaloids or Secologanin Tryptamine Alkaloids
Bisindole alkaloids
Distribution in nature
Biosynthesis
Physiological activity
Applications
References
Bibliography

History
The action of some indole alkaloids has been known for ages. Aztecs used the psilocybin mushrooms which
contain alkaloids psilocybin and psilocin. The flowering plant Rauwolfia serpentina which contains reserpine
was a common medicine in India around 1000 BC. Africans used the roots of the perennial rainforest shrub
Iboga, which contain ibogaine, as a stimulant. An infusion of Calabar bean seeds was given to people accused of
crime in Nigeria: its rejection by stomach was regarded as a sign of innocence, otherwise, the person was killed
via the action of physostigmine, which is present in the plant and which causes paralysis of the heart and
lungs.[3]

Consumption of rye and related cereals contaminated with the fungus Claviceps purpurea causes ergot
poisoning and ergotism in humans and other mammals. The relationship between ergot and ergotism was
Pierre Joseph Pelletier
established only in 1717, and the alkaloid ergotamine, one of the main active ingredients of ergot, was isolated in
(1788–1842), discoverer
1918.[4]
of strychnine and one of
the founders of alkaloid
The first indole alkaloid, strychnine, was isolated by Pierre Joseph Pelletier and Joseph Bienaimé Caventou in
chemistry
1818 from the plants of the genus Strychnos. 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.[5][6] Indole itself was first obtained by Adolf von Baeyer in 1866 while decomposing Indigo.[7]

Classification
Depending on their biosynthesis, two types of indole alkaloids are distinguished; isoprenoids and non-isoprenoids. The latter include terpenoid
structural elements, synthesized by living organisms from dimethylallyl pyrophosphate (DMAPP) and/or isopentenyl pyrophosphate (IPP):[8]

◾ Non-isoprenoid:

◾ Simple derivatives of indole

◾ Simple derivatives of β-carboline
◾ Pyrroloindole alkaloids
◾ Indole-3-carbinol
 ◾ Indole-3-acetic acid
◾ Tryptamines
◾ Carbazoles
◾ Isoprenoid:

◾ hemiterpenoids: ergot alkaloids

◾ monoterpenoids.
◾ Strictosidine
◾ Catharanthine
◾ Yohimbine
◾ Vinca
◾ Strychnine
◾ Ellipticine

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.[9] Some 200 dimeric indole alkaloids are known with two indole groups.[10]

Non-isoprenoid indole alkaloids

The number of known non-isoprenoid indole alkaloids is small compared to the
number of indole alkaloids.[2]

Simple indole derivatives

Tryptamine
One of the simplest and yet widespread indole derivatives are the biogenic amines
β-carboline
tryptamine and 5-hydroxytryptamine (serotonin).[11] Although their assignment to
the alkaloid is not universally accepted,[12] they are both found in plants and
animals.[13] The tryptamine skeleton is part of the vast majority of indole
alkaloids.[14] For example, N,N-dimethyltryptamine (DMT), psilocin and its
Harmine
Serotonin phosphorylated psilocybin are the simplest derivatives of tryptamine.[13] Some
simple indole alkaloids do not contain tryptamine, such as gramine and glycozoline
(the latter is a derivative of carbazole).[15] Camalexin is a simple indole alkaloid
produced by the plant Arabidopsis thaliana, often used as a model for plant
Physostigmine biology.[16]
Canthinone

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[17] and a slightly more complex
structure of canthinone.[18] Harmaline was first isolated in 1838 by Göbel[19] and harmine in 1848 by Fritzche.[20][21][22]

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 physostigmine,[23] which was isolated by Jobst and Hesse in 1864.[24][25]

Isoprenoid indole alkaloids

Isoprenoid indole alkaloids include residues of tryptophan or tryptamine and isoprenoid building blocks derived from the dimethylallyl
pyrophosphate and isopentenyl pyrophosphate.[2]

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 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:[26][27]

◾ Water-soluble aminoalcohol derivatives, such as ergometrine and its isomer ergometrinine

◾ Water-insoluble polypeptide derivatives:

◾ Ergotamine group, including ergotamine, ergosine and their isomers

◾ Ergoxine groups, including ergostine, ergoptine, ergonine and their isomers
 ◾ Ergotoxine group, including 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.[27]

Monoterpenoid Indoles Alkaloids or Secologanin Tryptamine Alkaloids

Most monoterpenoid alkaloids include a 9 or 10 carbon fragment (bold in image) (originating from the
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
Structure of lysergic acid
catarantine. The circled carbon atoms are missing in the alkaloids which contain the C9 fragment instead of – the tryptophan
C10.[14] fragment is colored in
yellow and the
isoprenoid part from
DMAPP is blue

Corynanthe alkaloids include the unaltered skeleton of secologanin, which is modified in Iboga and Aspidosperma alkaloids.[28] Some
representative monoterpenoid indole alkaloids:[5][29][30]

Number of carbon atoms in the monoterpenoid fragment

Type
C9 C10

Corynanthe Ajmaline, aquamycin, strychnine, brucine Ajmalicine, yohimbine, reserpine, sarpagin, mitragynine

Iboga Ibogaine, ibogamine Voacangine, catharanthine

Aspidosperma Eburnamin Tabersonine, vindolin, vincamine

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.[31]

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:[32]

◾ Mannich reaction (voacamine)

◾ Michael reaction (villalstonine)
◾ Condensation of aldehydes with amines (toxiferine, calebassine)
◾ Oxidative coupling of tryptamines (calicantine);
◾ Splitting of the functional group of one of the monomers (vinblastine, vincristine).

Voacamine Villalstonine Toxiferine Vinblastine

Apart from bisindole alkaloids, dimeric alkaloids exist which are formed via dimerization of the indole monomer with another type of alkaloid.
An example is tubulosine consisting of indole and isoquinoline fragments.[33]

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.[34] Some members of the family Convolvulaceae, in
particular Ipomoea violacea and Turbina corymbosa, contain ergolines and lysergamides.[35] Despite the considerable structural diversity,
most of monoterpenoid indole alkaloids is localized in three families of dicotyledon plants: Apocynaceae (genera Alstonia, Aspidosperma,
Rauwolfia and Catharanthus), Rubiaceae (Corynanthe) and Loganiaceae (Strychnos).[36][37]

Indole alkaloids are also present in fungi. For example, psilocybin mushrooms contains derivatives of tryptamine and Claviceps contains
derivatives of lysergic acid.[34] 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.[38] Serotonin, which is an important neurotransmitter in
mammals, can also be attributed to simple indole alkaloids.[39]

Harmal contains β-carboline Ipomoea violacea contains Alstonia macrophylla contains Rauwolfia serpentina contains
alkaloids ergolines Corynanthe alkaloids Corynanthe alkaloids

Catharanthus roseus contains Psilocybe cubensis contains Ergot contains ergolines Colorado River toad (Bufo
monoterpenoid indole alkaloids psilocybin and psilocin alvarius) contains bufotenin
and 5-MeO-DMT

Biosynthesis
Biogenetic precursor of all indole alkaloids is the amino acid tryptophan. For most of them, the first synthesis step is decarboxylation of
tryptophan to form tryptamine. Dimethyltryptamine (DMT) is formed from tryptamine by methylation with the participation of coenzyme of S-
adenosyl methionine (SAM). Psilocin is produced by spontaneous dephosphorylation of psilocybin[40].

In the biosynthesis of serotonin, the intermediate product is not tryptamine but 5-hydroxytryptophan, which is in turn decarboxylated to form
5-hydroxytryptamine (serotonin).[13]

Biosynthesis of β-carboline alkaloids occurs through the formation of Schiff base from tryptamine and aldehyde (or keto acid) and subsequent
intramolecular Mannich reaction, where the C(2) carbon atom of indole serves as a nucleophile. Then, the aromaticity is restored via the loss of
a proton at the C(2) atom. The resulting tetrahydro-β-carboline skeleton then gradually oxidizes to dihydro-β-carboline and β-carboline. In the
formation of simple β-carboline alkaloids, such as harmine and harmaline, pyruvic acid acts as the keto acid. In the synthesis of monoterpenoid
indole alkaloids, secologanin plays the role of the aldehyde. Pirroloindole alkaloids are synthesized in living organisms in a similar way.[41]
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.[42]

Biosynthesis of monoterpenoid indole alkaloids begins with the Mannich reaction of tryptamine and secologanin; it yields strictosidine which is
converted to 4,21-dehydrogeissoschizine. Then, the biosynthesis of most alkaloids containing the unperturbed monoterpenoid part
(Corynanthe type) proceeds through cyclization with the formation of cathenamine and subsequent reduction to ajmalicine in the presence of
nicotinamide adenine dinucleotide phosphate (NADPH). In the biosynthesis of other alkaloids, 4,21-dehydrogeissoschizine first converts into
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 are produced in the reaction involving catarantine (alkaloid of type
Iboga) and vindolin (type Aspidosperma).[29][43]

Physiological activity
Indole alkaloids act on the central and peripheral nervous systems. Besides, bisindole alkaloids vinblastine and vincristine show antineoplastic
effect.[44]
Because of structural similarities with serotonin, many tryptamines can interact with serotonin 5-
HT receptors.[45] The main effect of the serotonergic psychedelics such as LSD, DMT, and psilocybin
is related to them being agonists of the 5-HT2A receptors.[46][47] In contrast, gramine is an
antagonist of the 5-HT2A receptor.[48]

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).[49][50] So ergotamine is a partial agonist of α- Tryptamine (left) and
adrenergic and 5-HT2 receptors, and thus narrows blood vessels and stimulates constriction of the phenethylamine (right) moieties of
uterus. Dihydroergotamine is more selective to α-adrenergic receptors and has a weaker effect on the lysergic acid molecule
serotonin receptors. Ergometrine is an agonist of α-adrenergic, 5-HT2 and partly D2
receptors.[50][51] Compared with other ergot alkaloids, ergometrine has a greater selectivity in
stimulating the uterus.[51] 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.[52][53]

Some monoterpenoid indole alkaloids also interact with adrenoceptors. For example, ajmalicine is a selective antagonist of α1-adrenergic
receptors and therefore has antihypertensive action.[54][55] Yohimbine is more selective to α2 adrenoceptor;[55] by blocking presynaptic α2-
adrenoceptors, it increases the release of norepinephrine thereby raising the blood pressure. Yohimbine was used for the treatment of erectile
dysfunction in men until emergence of more efficient drugs.[56]

Some alkaloids affect the turnover of monoamines indirectly. So, harmine and harmaline are reversible selective inhibitors of monoamine
oxidase-A.[57] Reserpine reduces concentration of monoamines in presynaptic and synaptic neurons, thereby inducing antihypertensive and
antipsychotic effects.[54]

Some indole alkaloids interact with other types of receptors. Mitragynine is an agonist of the μ-opioid receptor.[30] Harmal alkaloids are
antagonists to the GABAA-receptor,[58] and ibogaine – to NMDA-receptors.[59] Physostigmine is a reversible acetylcholinesterase inhibitor.[60]

Applications
Plants and fungi that contain indole alkaloids have a long history of use in traditional medicine. Rauwolfia
serpentina, which contains reserpine as the active substance, was used for over 3000 years in India to treat snake
bites and insanity.[61] In medieval Europe, extracts of ergot were used in medical abortion.[62]

Later, the plants were joined by pure preparations of indole alkaloids. Reserpine was the second (after
chlorpromazine) antipsychotic drug; however, it showed relatively weak action and strong side effects, and is not
used for this purpose any longer.[63] Instead, it is prescribed as an antihypertensive drug, often in combination with
other substances.[64]

Other drugs that affect the cardiovascular system include ajmaline, which is a Class I antiarrhythmic agents,[65] and Methylergometrine
ajmalicine, which is used in Europe as an antihypertensive drug.[54] Physostigmine – an inhibitor of maleate
acetylcholinesterase – and its synthetic analogs are used in the treatment of glaucoma, Alzheimer's disease (Methergin)
(rivastigmine) and myasthenia (neostigmine, pyridostigmine, distigmine).[66] Ergot alkaloids ergometrine
(ergobazin, ergonovine), ergotamine and their synthetic derivatives (methylergometrine) are applied against uterine
bleeding,[67] and bisindole alkaloids vinblastine and vincristine are antitumor agents.[68]

Animal studies have shown that ibogaine has a potential in treating heroin, cocaine, and alcohol addictions, which is associated with the
ibogaine antagonism to NMDA-receptors. Medical use of ibogaine is hindered by its legal status, as it is banned in many countries as a powerful
psychedelic drug with dangerous implications of overdose. However, illegal network in Europe and United States provide ibogaine for treating
drug addiction.[69][70]

Since ancient times, plants containing indole alkaloids have been used as psychedelic drugs. The Aztecs used
and the Mazatec people continue to use psilocybin mushrooms and the psychoactive seeds of morning glory
species like Ipomoea tricolor.[71] Amazonian tribes use the psychedelic infusion, ayahuasca, made from
Psychotria viridis and Banisteriopsis caapi.[72] 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 of DMT in the digestive
tract and liver, so it can cross the blood–brain barrier, whereas the direct effect of harmala alkaloids on the LSD blotters
central nervous system is minimal.[73] 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.[74] One of the most common
recreational psychedelic drugs, LSD, is a semi-synthetic ergoline (which contains the indole moiety).[75]

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