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| Formula | C14H16N2 |
| Molar mass | 212.296 g·mol−1 |
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Ergoline is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized inergot. Some of these are implicated in the condition ofergotism, which can take a convulsive form[1] or a gangrenous form. Even so, many ergoline alkaloids have been found to be clinically useful. Annual world production of ergot alkaloids has been estimated at 5,000–8,000 kg of all ergopeptines and 10,000–15,000 kg oflysergic acid, used primarily in the manufacture of semi-synthetic derivatives.[2]
Others, such aslysergic acid diethylamide, better known as LSD, asemi-synthetic derivative, andergine, a natural derivative found inArgyreia nervosa,Ipomoea tricolor and related species, are knownpsychedelic substances.[3]
Ergoline alkaloids are found infungi such as Claviceps purpurea, Claviceps paspali,[4][5] and the related Periglandula, which have a permanent, symbiotic bond with numerous flowering vines, most notably,Turbina corymbosa andIpomoea tricolor (“morning glory”).[6] Ergolines are concentrated in the seeds,[7] which have been used for ages by indigenous central/south Americans[8] (i.e. T. corymbosa seeds are known asololiuhqui[9][10]) The principal alkaloids in the seeds appear to beergine andisoergine, but they're just decomposition products oflysergic acid hydroxyethylamide, isolysergic hydroxyethylamide,lysergic acid hydroxymethylethylamide (syn.ergonovine), and isolysergic acid hydroxymethylethylamide (syn.ergonovinine).[11][12][13][14][15][16][17] All of the other ergolines have been quantified in very small amts. except for penniclavine, which was found to be the predominant ergoline in a 2016 assay of I. tricolor seeds.[18] Ergolines have been identified in 42 Morning Glory species.[19] The only ergolines of these seeds that have been trialed as isolates areergine,ergonovine, and lysergol, with lysergol showing the weakest effect[20] (refs:Ergine / Psychedelic Effects,Ergometrine / Psychedelic Effects).
Ergolinealkaloids were first isolated fromergot, a fungus that infects rye and causesergotism or St. Anthony's fire.[21] Reports of the toxic effects due to ergoline alkaloids date back to the 12th century.[22] Ergot also has a long history of medicinal use, which led to attempts to characterize its activity chemically. First reports of its use date back to 1582, where preparations of ergot were used in small doses by midwives to induce strong uterine contractions.[2][22] The first use of ergoline alkaloids in modern medicine was described in 1808 by John Stearns, an American physician, who had reported on the uterine contractile actions of a preparation of ergot as a remedy for "quickening birth".[2]
Attempts to characterize the activity of ergoline alkaloids began in 1907, with the isolation of ergotoxine by G. Barger and F. H. Carrin.[23] However, the industrial production of ergot alkaloids didn't begin until 1918, whenArthur Stoll patented the isolation ofergotamine tartrate, which was marketed bySandoz in 1921. Following the determination of the basicchemical structure of the ergot alkaloids in 1930, an era of intensive exploration of synthetic derivatives began and industrial production of ergoline alkaloids exploded, with Sandoz continuing to be the leading company in their production worldwide, up until 1950 when other competitors arose.[2][23] The company, now renamedNovartis, still retains its leadership in the product of ergot alkaloids. In 1943, Arthur Stoll andAlbert Hofmann reported the first total synthesis of an ergot alkaloid, ergometrine.[24] Though the synthesis found no industrial application, this was a huge leap forward in the industry.
There are a variety of clinically useful ergoline derivatives for the purpose ofvasoconstriction, the treatment ofmigraines, and treatment ofParkinson's disease. Ergoline alkaloids found their place in pharmacology long before modern medicine as preparations of ergot were often used by midwives in the 12th century to stimulate childbirth.[25] Following Arthur Stoll's isolation of ergometrine, the therapeutic use of ergoline derivatives became well explored.
The induction of uterine contractions via the preparation of ergot was attributed toergonovine, an ergoline derivative found in ergot, which is a powerfuloxytocic. From this,methergine, a synthetic derivative, was elucidated.[22] While used to facilitate child birth, ergoline derivatives can pass intobreast milk and should not be used during breastfeeding.[26] They are uterine contractors that can increase the risk of miscarriage during pregnancy.[9]
Another example of medically relevant ergoline alkaloids isergotamine, an alkaloid also found in ergot. It acts as avasoconstrictor and has been reported to controlmigraines. From ergotamine, theanti-migraine drugsdihydroergotamine andmethysergide were developed by Albert Hofmann.[27]
Ergoline derivatives, such ashydergine, a mixture of dihydroergotoxine mesylates or ergoline mesylates, have also been used in the treatment of dementia. The use of these alkaloids in the treatment ofParkinson's disease has also been prominent. Drugs such asbromocriptine act as a dopamine receptoragonist, stimulating the nerves that control movement.[28] Newer synthetic ergoline derivatives that have been synthesized for the treatment of Parkinson's disease includepergolide andlisuride, which both act asdopamine agonists as well.[28]
A famous ergoline derivative is thepsychedelic drugLSD, asemi-synthetic ergoline alkaloid that was discovered by Albert Hofmann. LSD is considered aSchedule I controlled substance.Ergometrine andergotamine are included as schedule I precursors in theUnited Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[29]
The mechanism of ergoline alkaloids varies for each derivative. A variety of modifications can be made to the ergoline skeleton to produce medically relevant derivatives. Types of potential ergoline-based drugs includedopaminergic,antidopaminergic,serotonergic, andantiserotonergic.[30] Ergoline alkaloids often interfere with multiple receptor sites, leading to negative side effects and adding to the challenge of drug development.
Ergolines, such as ergotoxin, have been reported to inhibit the deciduoma reaction, which is reversed through injection of progesterone. Thus, it was concluded that ergotoxin, and related ergolines, act via thehypothalamus andpituitary gland to inhibit thesecretion ofprolactin.[30] Drugs such asbromocriptine interact with the dopaminergic receptor sites as agonists with selectivity for D2 receptors, making them effective in treating Parkinson's disease. While the part of the ergoline alkaloid structure responsible for dopaminergic properties has yet to be identified, some reason that it is due to the pyroleethylamine moiety while others assert that it is due to the indoleethylamine partial structure.[30]
Antidopaminergic ergolines have found use inantiemetics and in the treatment ofschizophrenia. These substances areneuroleptic and are either an antagonist of dopamine at the postsynaptic level at the D2 receptor site or an agonist of dopamine at the presynaptic level at the D1 receptor site.[30] The antagonist or agonist behavior of the ergolines are substrate dependent and mixed agonist/antagonist behaviors of ergoline derivatives have been reported.[30]
The primary challenges of developing serotonergic/antiserotonergic ergolines is attributed toserotonin, or 5-HT, acting on various distinct receptor sites. Similarly, ergoline alkaloids have been shown to exhibit both 5-HT agonist and antagonist behaviors for multiple receptors, such asmetergoline, a 5-HT1A agonist/5-HT2A antagonist, andmesulergine, a 5-HT2A/2C antagonist.[30] The selectivity and affinity of ergolines for certain 5-HT receptors can be improved by introducing a bulky group on the phenyl ring of the ergoline skeleton, which would prevent the interaction of ergoline derivatives with receptors.[30] This methodology has been used to develop selective 5-HT1A and 5-HT2A ergolines in particular.
There are three main classes of ergoline derivatives, orsubstituted ergolines: (1) the water-solubleamides oflysergic acid (i.e.,lysergamides); (2) the water-insolubleergopeptines (i.e.,ergopeptides); and (3) theclavine group.[31] Only the lysergamides have been known to havepsychedelic effects.[32][33]
The relationship between these compounds is summarized in the followingstructural formula and table of substitutions.
| Name | R1 | R2 | R3 |
|---|---|---|---|
| Ergine | H | H | H |
| Ergonovine | H | CH(CH3)CH2OH | H |
| Methergine | H | CH(CH2CH3)CH2OH | H |
| Methysergide | CH3 | CH(CH2CH3)CH2OH | H |
| LSD | H | CH2CH3 | CH2CH3 |
Peptide ergot alkaloids orergopeptines (also known asergopeptides) are ergoline derivatives that contain a tripeptide structure attached to the basic ergoline ring in the same location as theamide group of the lysergic acid derivatives. This structure consists ofproline and two other α-amino acids, linked in an unusualcyclol formation >N-C(OH)< with the carboxyl carbon of proline, at the juncture between the twolactam rings.[34] Some of the important ergopeptines are summarized below.[35] In addition to the following ergopeptines, a commonly encountered term isergotoxine, which refers to a mixture of equal proportions ofergocristine,ergocornine and ergocryptine, the latter being a 2:1 mixture ofalpha- andbeta-ergocryptine. Ergopeptines are considered to be the most toxic and are capable of inducing gangrene: “The low molecular ergolines are lacking the complex peptide moiety, which is apparently responsible for the persistence of the ergopeptines at the receptor molecules.”[36]
| Name | R1 | R2 | R3 | Amino acid at R2 | Amino acid at R3 |
|---|---|---|---|---|---|
| Ergocristine | CH(CH3)2 | benzyl | Valine | Phenylalanine | |
| Ergocornine | CH(CH3)2 | CH(CH3)2 | Valine | Valine | |
| alpha-Ergocryptine | CH(CH3)2 | CH2CH(CH3)2 | Valine | Leucine | |
| beta-Ergocryptine | CH(CH3)2 | CH(CH3)CH2CH3 (S) | Valine | Isoleucine | |
| Ergotamine | CH3 | benzyl | Alanine | Phenylalanine | |
| Ergovaline | CH3 | CH(CH3)2 | Alanine | Valine | |
| alpha-Ergosine | CH3 | CH2CH(CH3)2 | Alanine | Leucine | |
| beta-Ergosine | CH3 | CH(CH3)CH2CH3 (S) | Alanine | Isoleucine | |
| Bromocriptine (semisynthetic) | Br | CH(CH3)2 | CH2CH(CH3)2 | Valine | Leucine |
A variety of modifications to the basic ergoline are seen in nature, for exampleagroclavine,elymoclavine,lysergol. Those deriving fromdimethylergoline are referred to as clavines. Examples of clavines, includefestuclavine,fumigaclavine A,fumigaclavine B andfumigaclavine C.
Some synthetic ergoline derivatives do not fall easily into any of the above groups. Some examples are:
"Clavines are thought to contribute substantially to convulsive ergotism, sinceC. fusiformis ergots, which possess clavines, but no [lysergic acid] or lysergyl amides, cause convulsive symptoms (26). However, the ergopeptines are known to produce similar symptoms, and are also thought to cause gangrenous ergotism (6). The occurrence of convulsive ergotism without dry gangrene suggests that other clavine or lysergyl alkaloids are involved, or that individual effects of specific ergopeptines may give clinically different syndromes (6)."
II. Through the Ages: A History of Ergot Alkaloid Use, Abuse, and Poisoning, p. 50
{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
"Whereas ergine, lysergic acid hydroxyethylamide, and lysergyl L-valine methylester occur in ergot of rye only in trace amounts, ergonovine (synonyms ergometrine, ergobasin), which is the specific oxytocic factor of a ergot, is often found in remarkable quantities. In contrast, ergine and hydroxyethylamide of lysergic acid are the main constituents of certain ergot growing on wild grasses, e.g. Paspalum distichum." 4. Plants of Hallucinogenic Use / The Fungi, p. 37
"We analyzed ergot of wheat and ergot of barley in our laboratory and they were found to contain basically the same alkaloids as ergot of rye, viz. alkaloids of the ergotamine and ergotoxine group, ergonovine, and sometimes also traces of lysergic acid amide. As I said before, ergonovine and lysergic acid amide, both psychoactive, are soluble in water whereas the other alkaloids are not." Albert Hofmann, 2. A Challenging Question and my Answer, p. 42
"ergine and ergometrine concentration is 12-fold lower in plant samples than in seeds." Analysis of IP-HB2 young plants
"Ololiuhqui was far more prominent as an entheogen here in Mesoamerica than those mushrooms; the mushrooms are mentioned only here and there by a few competent chroniclers; yet almost an entire book was devoted to denouncing mainly the ololiuhqui idolatry. The annals of the Inquisition contain many times more autos de fe for ololiuhqui than for mushrooms." Jonathan Ott, quoted in 15. Mixing the Kykeon Anew (section: Ergine)
"These compounds, although well documented as components in the Convolvulaceae, are possibly lost in several of the analyses of alkaloid composition. They are extremely unstable, and are very readily degraded into acetaldehyde and the corresponding amide, ergine or isoergine." (p. 72)
"Later, it was found that ergine and isoergine were present in the seeds to some extent in the form of lysergic acid N-(1-hydroxyethyl) amide and isolysergic acid N-(1-hydroxyethyl) amide, respectively, and that, during the isolation procedure, they easily hydrolize to ergine and isoergine, respectively, and acetaldehyde." 4. Plants of Hallucinogenic Use / Convolvulaceae, p. 246
See Table 3 under "Analysis of different Ipomoea seeds".
Concentration values for "LSH", "Lyzergol/isobars", penniclavine, and chanoclavine can be obtained by dividing the concentration values of ergine or ergometrine by their relative abundance values and multiplying that number by the relative abundance value of the specified chemical.
{{cite journal}}: CS1 maint: postscript (link)3.1 Amide Modifications of Lysergic Acid Derivatives The simplest ergoline with human psychoactive properties is lysergic acid amide (23, ergine), reported by Hofmann and Tscherter to be the active component in Rivea corymbosa seeds used by the Aztecs in various magical potions and ointments (Hofmann 1971). [...]
Studies of the Amide Portion of Lysergic Acid Derivatives The simplest ergoline with human psychoactive properties, and presumably 5-HT2A agonist activity, is lysergic acid amide (15, ergine), which was reported by Hofmann and Tscherter36 to be the active component in Rivea corymbosa seeds, used by the Aztecs in various magical potions and ointments (Figure 12). [...]
"The low molecular ergolines are lacking the complex peptide moiety, which is apparently responsible for the persistence of the ergopeptines at the receptor molecules." 4.2.5.1 Mechanisms of Action and Therapeutic Relevance, p. 249