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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. 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.
Consumption of rye and related contaminated with the fungus Claviceps purpurea causes 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.Hesse, pp. 333–335.
The first indole alkaloid, strychnine, was isolated by Pierre Joseph Pelletier and Joseph Bienaimé Caventou in 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.Hesse, p. 316.Orekhov, p. 616 Indole itself was first obtained by Adolf von Baeyer in 1866 while decomposing Indigo dye..
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.Hesse, pp. 14–30. Some 200 dimeric indole alkaloids are known with two indole groups.Hesse, pp. 91–92.
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.
Corynanthe alkaloids include the unaltered skeleton of secologanin, which is modified in Iboga alkaloids and Aspidosperma alkaloids.Dewick, p. 351 Some representative monoterpenoid indole alkaloids:Dewick, pp. 350–359
| 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.Hesse, p. 30
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.Hesse, p. 99
Indole alkaloids are also present in fungi. For example, Psilocybe stuntzii contains derivatives of tryptamine and Claviceps purpurea 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, which is an important neurotransmitter in mammals, can also be attributed to simple indole alkaloids.Waksmundzka, p. 625
File:Crape Jasmine.jpg| Tabernaemontana divaricata contains indole alkaloids including catharanthine, conophylline, ibogamine, tabersonine and voacristine
File:Pcubmazatapec.jpg | Psilocybe cubensis contains psilocybin and psilocin
File:Claviceps purpurea.JPG|Ergot contains ergotamine.
File:2009-03-13Bufo alvarius071.jpg|The Colorado River toad ( Bufo alvarius) secretes bufotenin and 5-MeO-DMT from specialized .
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 beta 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.Dewick, pp. 349, 365
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.Dewick, pp. 369–370
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 catharanthine (alkaloid of type Iboga) and vindolin (type Aspidosperma).
Because of structural similarities with serotonin, many tryptamines can interact with serotonin 5-HT receptors. The main effect of the serotonergic psychedelics such as LSD, DMT, and psilocybin is related to them being of the 5-HT2A receptors.Alper, p. 8 In contrast, gramine is an antagonist of the 5-HT2A receptor.
, 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).Dewick, pp. 374–375 So ergotamine is a partial agonist of α-adrenergic and 5-HT2 receptors, and thus Vasoconstriction blood vessels and stimulates constriction of the uterus. Dihydroergotamine is more selective to α-adrenergic receptors and has a weaker effect on serotonin receptors. Ergometrine is an agonist of α-adrenergic, 5-HT2 and partly D2 receptors. Compared with other ergot alkaloids, ergometrine has a greater selectivity in stimulating the uterus. LSD, a 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 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 Chemical synapse 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 .Alper, p. 7 Physostigmine is a reversible acetylcholinesterase inhibitor.Dewick, p. 367
Later, the plants were joined by pure preparations of indole alkaloids. Reserpine was the second (after chlorpromazine) antipsychotic drug; however, it showed relatively weak action and strong side effects, and is not used for this purpose any longer. Instead, it is prescribed as an antihypertensive drug, often in combination with other substances.
Other drugs that affect the cardiovascular system include ajmaline, which is a Class I antiarrhythmic agents, and ajmalicine, which is used in Europe as an antihypertensive drug. Physostigmine – an inhibitor of acetylcholinesterase – and its synthetic analogs are used in the treatment of glaucoma, Alzheimer's disease (rivastigmine) and Muscle weakness (neostigmine, pyridostigmine, distigmine).Dewick, pp. 367–368 Ergot alkaloids ergometrine (ergobazin, ergonovine), ergotamine and their synthetic derivatives (methylergometrine) are applied against uterine bleeding, and bisindole alkaloids vinblastine and vincristine are antitumor agents.
Animal studies have shown that ibogaine has a potential in treating heroin, cocaine, and alcohol addictions, which is associated with the ibogaine antagonism to . 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.Alper, pp. 2–19Dewick, p. 357
Since ancient times, plants containing indole alkaloids have been used as . The used and the Mazatec people continue to use psilocybin mushrooms and the psychoactive seeds of morning glory species like Ipomoea tricolor.Dewick, p. 348 Amazonian tribes use the psychedelic infusion, ayahuasca, made from Psychotria viridis and Banisteriopsis caapi.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 , which act as monoamine oxidase inhibitors. It is believed that the main function of the harmala alkaloids in ayahuasca is to prevent the Metabolism 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 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 , LSD, is a semi-synthetic ergoline (which contains the indole moiety).Dewick, p. 376
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