View source for Ergoline

{{Short description|Chemical compound}}
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| IUPAC_name         = (6a''R'')-4,6,6a,7,8,9,10,10a-Octahydroindolo[4,3-''fg'']quinoline
| image              = Ergoline Structural Formulae V.1.svg
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| image2             = 3D ergoline molecule animation.gif
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| smiles             = [H][C@@]34Cc1c[nH]c2cccc(c12)[C@@]3([H])CCCN4
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| StdInChI           = 1S/C14H16N2/c1-3-11-10-4-2-6-15-13(10)7-9-8-16-12(5-1)14(9)11/h1,3,5,8,10,13,15-16H,2,4,6-7H2/t10-,13-/m1/s1
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'''Ergoline''' is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized in [[ergot]]. Some of these are implicated in the condition of [[ergotism]], which can take a convulsive form<ref>{{cite journal | vauthors = Schardl CL, Panaccione DG, Tudzynski P | title = Ergot alkaloids--biology and molecular biology | journal = The Alkaloids. Chemistry and Biology | volume = 63 | pages = 45–86 | date = 2006 | pmid = 17133714 | doi = 10.1016/s1099-4831(06)63002-2 | publisher = Elsevier | isbn = 978-0-12-469563-4 | quote =  <br/>“Clavines are thought to contribute substantially to convulsive ergotism, since ''C. 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'').”<br/>II. Through the Ages: A History of Ergot Alkaloid Use, Abuse, and Poisoning, p. 50 }}</ref> 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&nbsp;kg of all ergopeptines and 10,000–15,000&nbsp;kg of [[lysergic acid]], used primarily in the manufacture of semi-synthetic derivatives.<ref name=":02">{{cite journal | vauthors = Schiff PL | title = Ergot and its alkaloids | journal = American Journal of Pharmaceutical Education | volume = 70 | issue = 5 | pages = 98 | date = October 2006 | pmid = 17149427 | pmc = 1637017 | doi = 10.5688/aj700598 | doi-broken-date = 28 January 2025 }}</ref>

Others, such as [[lysergic acid diethylamide]], better known as LSD, a [[Semisynthesis|semi-synthetic]] derivative, and [[ergine]], a natural derivative found in ''[[Argyreia nervosa]]'', ''[[Ipomoea tricolor]]'' and related species, are known [[Psychedelic drug|psychedelic]] substances.<ref>{{cite journal | vauthors = Juszczak GR, Swiergiel AH | title = Recreational use of D-lysergamide from the seeds of Argyreia nervosa, Ipomoea tricolor, Ipomoea violacea, and Ipomoea purpurea in Poland | journal = Journal of Psychoactive Drugs | volume = 45 | issue = 1 | pages = 79–93 | year = 2013 | pmid = 23662334 | doi = 10.1080/02791072.2013.763570 | s2cid = 22086799 }}</ref>

==Natural occurrence==
Ergoline alkaloids are found in [[fungi]] such as Claviceps purpurea, Claviceps paspali,<ref name=":0">{{Cite book | vauthors = Schultes R |title=The Botany and Chemistry of Hallucinogens |publisher=Charles Thomas |year=1973 |isbn=9780398064167 |location=Springfield, IL |language=En | chapter = 4. Plants of Hallucinogenic Use / The Fungi | page =  37
|quote = <br>“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
}}</ref><ref>{{Cite book | vauthors = Wasson RG, Hofmann A, Ruck CA, Webster P |url=https://books.google.com/books?id=7JC7EAAAQBAJ&pg=PA42 |title=The Road to Eleusis: Unveiling the Secret of the Mysteries |publisher=North Atlantic Books |isbn=978-1-55643-752-6 | veditors = Forte R |edition=30th Anniversary |location=Berkeley, Calif. |publication-date=November 25, 2008 |orig-date=1978 |language=En
|quote = <br>“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
}}</ref> and the related Periglandula, which have a permanent, symbiotic bond with numerous flowering vines, most notably, ''[[Turbina corymbosa]]'' and ''[[Ipomoea tricolor]]'' (“morning glory”).<ref>{{cite book | vauthors = Leistner E, Steiner U | chapter = The Genus Periglandula and Its Symbiotum with Morning Glory Plants (Convolvulaceae) |publication-date=February 3, 2018 | veditors = Anke T, Schüffler A | title = Physiology and Genetics |pages=131–147 |chapter-url= http://link.springer.com/10.1007/978-3-319-71740-1_5 |access-date=2024-11-21 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-319-71740-1_5 |isbn=978-3-319-71739-5 }}</ref> Ergolines are concentrated in the seeds,<ref>{{cite journal | vauthors = Nowak J, Woźniakiewicz M, Klepacki P, Sowa A, Kościelniak P | title = Identification and determination of ergot alkaloids in Morning Glory cultivars | journal = Analytical and Bioanalytical Chemistry | volume = 408 | issue = 12 | pages = 3093–3102 | date = May 2016 | pmid = 26873205 | pmc = 4830885 | doi = 10.1007/s00216-016-9322-5 | quote =  <br>“ergine and ergometrine concentration is 12-fold lower in plant samples than in seeds.” Analysis of IP-HB2 young plants }}</ref> which have been used for ages by indigenous central/south Americans<ref>{{Cite book | vauthors = Ruck CA |title=Sacred Mushrooms of the Goddess: The Secrets of Eleusis |date=2006 |publisher=Ronin Publishing, Inc |isbn=978-1-57951-030-5 |location=Berkeley, California | quote = <br>“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)}}</ref> (i.e. T. corymbosa seeds are known as ''ololiuhqui''<ref name="Schardl20063">{{cite book|vauthors=Schardl CL, Panaccione DG, Tudzynski P|year=2006|title=Ergot alkaloids&nbsp;– biology and molecular biology|journal=The Alkaloids. Chemistry and Biology |series=The Alkaloids: Chemistry and Biology|volume=63|pages=45–86|doi=10.1016/S1099-4831(06)63002-2|isbn=978-0-12-469563-4|pmid=17133714}}</ref><ref>{{cite journal | vauthors = Carod-Artal FJ | title = Hallucinogenic drugs in pre-Columbian Mesoamerican cultures | journal = Neurologia | volume = 30 | issue = 1 | pages = 42–49 | year = 2015 | pmid = 21893367 | doi = 10.1016/j.nrl.2011.07.003 | doi-access = free }}</ref>) The principal alkaloids in the seeds appear to be [[ergine]] and [[isoergine]], but they're just decomposition products of [[lysergic acid hydroxyethylamide]], isolysergic hydroxyethylamide, [[ergonovine|lysergic acid hydroxymethylethylamide (syn. ''ergonovine'')]], and isolysergic acid hydroxymethylethylamide (syn. ''ergonovinine'').<ref>{{Cite book | vauthors = Shulgin A |chapter-url=https://books.google.com/books?id=yt2KcKcJROgC&pg=PA71 |title=Psychopharmacological agents |publisher=Academic Press |publication-date=2012-12-02 |orig-date=1976 |isbn=978-0-12-290559-9 | veditors = Maxwell G |series=Medicinal Chemistry |volume=4 |location=New York |pages=71–72 |chapter=4. Psychotomimetic Agents |quote = <br>“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)}}</ref><ref>{{Cite book | vauthors = Schultes RE, Hofmann A |title=The Botany and Chemistry of Hallucinogens  |publisher=Charles Thomas |year=1973 |isbn=9780398064167 |location=Springfield, IL |pages=246 |quote = <br>“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}}</ref><ref>{{Cite journal | vauthors = Flieger M, Sedmera P, Vokoun J, ((R̆ic̄icovā A)), ((R̆ehác̆ek Z)) |publication-date=1982-02-19 |title=Separation of four isomers of lysergic acid α-hydroxyethylamide by liquid chromatography and their spectroscopic identification |url=https://linkinghub.elsevier.com/retrieve/pii/S0021967300848955 |journal=Journal of Chromatography A |volume=236 |issue=2 |pages=441–452 |doi=10.1016/S0021-9673(00)84895-5 |issn=0021-9673|url-access=subscription }}</ref><ref>{{Cite journal | vauthors = Ramstad E |publication-date=1968 |title=Chemistry of alkaloid formation in ergot |journal=Lloydia |volume=31 |pages=327–341}}</ref><ref>{{cite journal | vauthors = Kleinerová E, Kybal J | title = Ergot alkaloids. IV. Contribution to the biosynthesis of lysergic acid amides | journal = Folia Microbiologica | volume = 18 | issue = 5 | pages = 390–392 | pmid = 4757982 | doi = 10.1007/BF02875934 | publication-date = September 1973 }}</ref><ref>{{cite journal | vauthors = Panaccione DG, Tapper BA, Lane GA, Davies E, Fraser K | title = Biochemical outcome of blocking the ergot alkaloid pathway of a grass endophyte | journal = Journal of Agricultural and Food Chemistry | volume = 51 | issue = 22 | pages = 6429–6437 | date = October 2003 | pmid = 14558758 | doi = 10.1021/jf0346859 | bibcode = 2003JAFC...51.6429P }}</ref><ref>{{cite book | vauthors = Panaccione DG | chapter = Ergot alkaloids | title = The Mycota, Industrial Applications | edition = 2nd | veditors = Hofrichter M | publisher = Springer-Verlag | location = Berlin-Heidelberg, Germany | date = 2010 | volume = 10 | pages = 195–214 }}</ref> 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.<ref name=nowak>{{cite journal | vauthors = Nowak J, Woźniakiewicz M, Klepacki P, Sowa A, Kościelniak P | title = Identification and determination of ergot alkaloids in Morning Glory cultivars | journal = Analytical and Bioanalytical Chemistry | volume = 408 | issue = 12 | pages = 3093–3102 | date = May 2016 | pmid = 26873205 | pmc = 4830885 | doi = 10.1007/s00216-016-9322-5 | quote =  <br>See Table 3 under “Analysis of different Ipomoea seeds”.<br>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. | publication-date = February 14, 2016 }}</ref> Ergolines have been identified in 42 Morning Glory species.<ref>{{Cite book | vauthors = Eich E |url=https://link.springer.com/book/10.1007/978-3-540-74541-9 |title=Solanaceae and convolvulaceae - secondary metabolites: biosynthesis, chemotaxonomy, biological and economic significance: a handbook |publisher=Springer-Verlag |isbn=978-3-540-74540-2 |location=Berlin, Heidelberg |publication-date=January 12, 2008 |language=En |chapter=4.2 Ergolines |doi=10.1007/978-3-540-74541-9 |oclc=195613136}}<br>Table 4.1 Unambiguously ergoline-positive Ipomoea species (pages 225-227)<br>Table 4.4 Unambiguously ergoline-positive Argyreia species (p. 236)<br>Table 4.5 Unambiguously ergoline-positive Stictocardia and Turbina species (p. 238)
</ref> The only ergolines of these seeds that have been trialed as isolates are [[ergine]], [[ergonovine]], and lysergol, with lysergol showing the weakest effect<ref>{{cite journal | vauthors = Heim E, Heimann H, Lukács G | title = Die psychische Wirkung der mexikanischen Droge "Ololiuqui" am Menschen | language = de | journal = Psychopharmacologia | volume = 13 | issue = 1 | pages = 35–48 | date = 1968 | pmid = 5675457 | doi = 10.1007/BF00401617 | postscript = <br>c) ᴅ-Lysergol<br><br>“Changes occurred only with a dosage of 8 mg, with a noticeable slowing of expression and behavior. The facial expression appeared flat, and speech showed a reduction in the five expressive qualities. Subjectively, fewer vegetative sensations were observed, but there was a marked inhibition of initiative.” 3. Results, p. 40<br>Translated from German with ChatGPT.}}</ref> (refs: [[Ergine#Psychedelic Effects|Ergine / Psychedelic Effects]], [[Ergometrine#Psychedelic Effects|Ergometrine / Psychedelic Effects]]).

==History==
Ergoline [[alkaloid]]s were first isolated from [[ergot]], a fungus that infects rye and causes [[ergotism]] or St. Anthony's fire.<ref>{{cite journal | vauthors = Gerhards N, Neubauer L, Tudzynski P, Li SM | title = Biosynthetic pathways of ergot alkaloids | journal = Toxins | volume = 6 | issue = 12 | pages = 3281–3295 | date = December 2014 | pmid = 25513893 | pmc = 4280535 | doi = 10.3390/toxins6123281 | doi-access = free }}</ref> Reports of the toxic effects due to ergoline alkaloids date back to the 12th century.<ref name=":12">{{cite journal | vauthors = de Groot AN, van Dongen PW, Vree TB, Hekster YA, van Roosmalen J | title = Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology | journal = Drugs | volume = 56 | issue = 4 | pages = 523–535 | date = October 1998 | pmid = 9806101 | doi = 10.2165/00003495-199856040-00002 | s2cid = 46971443 }}</ref> 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.<ref name=":02"/><ref name=":12"/> 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".<ref name=":02" />

Attempts to characterize the activity of ergoline alkaloids began in 1907, with the isolation of ergotoxine by G. Barger and F. H. Carrin.<ref name=":2">{{Cite book| vauthors = Sfetcu N |title=Health & Drugs - Disease, Prescription & Medication|publisher=Lulu.com|year=2014|isbn=9781312039995}}</ref> However, the industrial production of ergot alkaloids didn't begin until 1918, when [[Arthur Stoll]] patented the isolation of [[ergotamine tartrate]], which was marketed by [[Sandoz]] in 1921. Following the determination of the basic [[chemical 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.<ref name=":02" /><ref name=":2" /> The company, now renamed [[Novartis]], still retains its leadership in the product of ergot alkaloids. In 1943, Arthur Stoll and [[Albert Hofmann]] reported the first total synthesis of an ergot alkaloid, ergometrine.<ref>{{cite book | vauthors = Stoll A, Hofmann A | chapter = Chapter 21 The Ergot Alkaloids|date=1965| title = The Alkaloids: Chemistry and Physiology |volume=8 |pages=725–783 |publisher=Elsevier |language=en |doi=10.1016/s1876-0813(08)60060-3 |isbn=978-0-12-469508-5 }}</ref> Though the synthesis found no industrial application, this was a huge leap forward in the industry.

==Uses==
There are a variety of clinically useful ergoline derivatives for the purpose of [[vasoconstriction]], the treatment of [[migraine]]s, and treatment of [[Parkinson'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.<ref>{{Cite book|last=European Commission. Joint Research Centre.|title=Report on the 2017 proficiency test of the European Union reference laboratory for mycotoxins determination of ergot alkaloids in rye.|oclc=1060942360}}</ref> 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 to [[ergonovine]], an ergoline derivative found in ergot, which is a powerful [[oxytocic]]. From this, [[methergine]], a synthetic derivative, was elucidated.<ref name=":12"/> While used to facilitate child birth, ergoline derivatives can pass into [[breast milk]] and should not be used during breastfeeding.<ref name="kidsgrowth2">{{usurped|1=[https://archive.today/20070623011707/http://www.kidsgrowth.org/resources/articledetail.cfm?id=471 kidsgrowth.org --> Drugs and Other Substances in Breast Milk]}} Retrieved on June 19, 2009.</ref> They are uterine contractors that can increase the risk of miscarriage during pregnancy.<ref name="Schardl20063"/>

Another example of medically relevant ergoline alkaloids is [[ergotamine]], an alkaloid also found in ergot. It acts as a [[Vasoconstriction|vasoconstrictor]] and has been reported to control [[migraine]]s. From ergotamine, the [[anti-migraine]] drugs [[dihydroergotamine]] and [[methysergide]] were developed by Albert Hofmann.<ref>{{Cite book| vauthors = Winkelman M, Roberts TB |title=Psychedelic medicine : new evidence for hallucinogenic substances as treatments|date=2007|publisher=Praeger Publishers|isbn=978-0-275-99023-7|oclc=85813998}}</ref>

Ergoline derivatives, such as [[hydergine]], 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 of [[Parkinson's disease]] has also been prominent. Drugs such as [[bromocriptine]] act as a dopamine receptor [[agonist]], stimulating the nerves that control movement.<ref name=":3">{{cite journal | vauthors = Lataste X | title = The history and pharmacology of dopamine agonists | journal = The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques | volume = 11 | issue = 1 Suppl | pages = 118–123 | date = February 1984 | pmid = 6713309 | doi = 10.1017/S0317167100046266 | doi-access = free }}</ref> Newer synthetic ergoline derivatives that have been synthesized for the treatment of Parkinson's disease include [[pergolide]] and [[lisuride]], which both act as dopamine agonists as well.<ref name=":3" />

A famous ergoline derivative is the [[psychedelic drug]] [[LSD]], a [[Semisynthesis|semi-synthetic]] ergoline alkaloid that was discovered by Albert Hofmann. LSD is considered a [[Schedule I controlled substance]]. [[Ergometrine]] and [[ergotamine]] are included as schedule I precursors in the [[United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances]].<ref name="http://www.incb.org/pdf/e/list/red.pdf2">{{cite web | title = List of Precursors and Chemicals Frequently Used in the Illicit Manufacture of Narcotic Drugs and Psychotropic Substances Under International Control | edition = Eleventh | date = January 2007 | work = International Narcotics Control Board | location = Vienna, Austria | url = http://www.incb.org/pdf/e/list/red.pdf | archive-url = https://web.archive.org/web/20080227224025/http://www.incb.org/pdf/e/list/red.pdf | archive-date=2008-02-27}}.</ref>

== Mechanism of action ==
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 include [[dopaminergic]], [[antidopaminergic]], [[Serotonin|serotonergic]], and [[antiserotonergic]].<ref name=":4">{{cite journal | vauthors = Mantegani S, Brambilla E, Varasi M | title = Ergoline derivatives: receptor affinity and selectivity | journal = Farmaco | volume = 54 | issue = 5 | pages = 288–296 | date = May 1999 | pmid = 10418123 | doi = 10.1016/s0014-827x(99)00028-2 }}</ref> Ergoline alkaloids often interfere with multiple receptor sites, leading to negative side effects and adding to the challenge of drug development.

=== Dopaminergic/antidopaminergic ===
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 the [[hypothalamus]] and [[pituitary gland]] to inhibit the [[secretion]] of [[prolactin]].<ref name=":4" /> Drugs such as [[bromocriptine]] interact with the dopaminergic receptor sites as agonists with selectivity for D<sub>2</sub> 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.<ref name=":4" />

Antidopaminergic ergolines have found use in [[antiemetic]]s and in the treatment of [[schizophrenia]]. These substances are [[neuroleptic]] and are either an antagonist of dopamine at the postsynaptic level at the D<sub>2</sub> receptor site or an agonist of dopamine at the presynaptic level at the D<sub>1</sub> receptor site.<ref name=":4" /> The antagonist or agonist behavior of the ergolines are substrate dependent and mixed agonist/antagonist behaviors of ergoline derivatives have been reported.<ref name=":4" />

=== Serotonergic/antiserotonergic ===
The primary challenges of developing serotonergic/antiserotonergic ergolines is attributed to [[serotonin]], 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 as [[metergoline]], a 5-HT<sub>1A</sub> agonist/5-HT<sub>2A</sub> antagonist, and [[mesulergine]], a 5-HT<sub>2A/2C</sub> antagonist.<ref name=":4" /> 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.<ref name=":4" /> This methodology has been used to develop selective 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> ergolines in particular.

==Ergoline derivatives==
There are three main classes of ergoline derivatives, or ''substituted ergolines'': (1) the water-soluble [[amide]]s of ''[[lysergic acid]]'' (i.e., [[lysergamide]]s); (2) the water-insoluble ''ergopeptines'' (i.e., ''ergo[[peptides]]''); and (3) the ''clavine'' group.<ref name="Schardl2006">{{cite book|vauthors=Schardl CL, Panaccione DG, Tudzynski P |year=2006|title=Ergot alkaloids&nbsp;– biology and molecular biology|journal=The Alkaloids. Chemistry and Biology |volume=63|pages=45–86|pmid=17133714|doi=10.1016/S1099-4831(06)63002-2|series=The Alkaloids: Chemistry and Biology|isbn=978-0-12-469563-4}}</ref> Only the lysergamides have been known to have [[serotonergic psychedelic|psychedelic]] effects.<ref name="Nichols2018">{{cite book | vauthors = Nichols DE | title = Chemistry and Structure-Activity Relationships of Psychedelics | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = | quote = 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). [...] }}</ref><ref name="Nichols2012">{{cite journal | vauthors = Nichols DE | title=Structure–activity relationships of serotonin 5-HT2A agonists | journal=Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | volume=1 | issue=5 | date=2012 | issn=2190-460X | doi=10.1002/wmts.42 | doi-access=free | pages=559–579 | quote=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). [...] }}</ref>

===Lysergic acid amides===
{{Main|Substituted lysergamide}}

* [[Ergine]] (LSA, <small>D</small>-lysergic acid amide, LAA, LA-111)
** [[IUPAC name]]: 9,10-didehydro-6-methylergoline-8beta-carboxamide
** [[CAS number]]: {{CAS|478-94-4}}
* [[Ergonovine]] (ergobasine)
** [[International Nonproprietary Name|INN]]: ergometrine
** IUPAC name: (8beta(S))-9,10-didehydro-N-(2-hydroxy-1-methylethyl)-6-methyl-ergoline-8-carboxamide
** CAS number: {{CAS|60-79-7}}
* [[Methergine]] (ME-277)
** INN: methylergometrine
** IUPAC name: (8beta(S))-9,10-didehydro-N-(1-(hydroxymethyl)propyl)-6-methyl-ergoline-8-carboxamide
** CAS number: {{CAS|113-42-8}}
* [[Methysergide]] (UML-491)
** INN: methysergide
** IUPAC name: (8''beta'')-9,10-didehydro-''N''-(1-(hydroxymethyl)propyl)-1,6-dimethyl-ergoline-8-carboxamide
** CAS number: {{CAS|361-37-5}}
* [[LSD]] (<small>D</small>-lysergic acid diethylamide, LSD-25)
** INN: lysergide
** IUPAC name: (8beta)-9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-carboxamide
** CAS number: {{CAS|50-37-3}}
* [[Lysergic acid hydroxyethylamide|LSH]] (<small>D</small>-lysergic acid α-hydroxyethylamide)
** IUPAC name: 9,10-didehydro-N-(1-hydroxyethyl)-6-methylergoline-8-carboxamide
** CAS number: {{CAS|3343-15-5}}

The relationship between these compounds is summarized in the following [[structural formula]] and table of substitutions.

[[File:Ergine - Ergines.svg|left|Substituted ergine (structural formula)]]

{| class="wikitable" style="float:right"
!Name !! R<sup>1</sup> !! R<sup>2</sup> !! R<sup>3</sup>
|-
| [[Ergine]] || H || H || H
|-
| [[Ergonovine]] || H || CH(CH<sub>3</sub>)CH<sub>2</sub>OH || H
|-
| [[Methergine]] || H || CH(CH<sub>2</sub>CH<sub>3</sub>)CH<sub>2</sub>OH || H
|-
| [[Methysergide]] || [[methyl|CH<sub>3</sub>]] || CH(CH<sub>2</sub>CH<sub>3</sub>)CH<sub>2</sub>OH || H
|-
| [[LSD]] || H || [[Ethyl group|CH<sub>2</sub>CH<sub>3</sub>]] || CH<sub>2</sub>CH<sub>3</sub>
|}

{{clear}}

===Peptide alkaloids===<!-- Ergotoxine, Ergopeptine and other titles redirect here -->
Peptide ergot alkaloids or '''[[ergopeptines]]''' (also known as ''ergopeptides'') are ergoline derivatives that contain a tri[[peptide]] structure attached to the basic ergoline ring in the same location as the [[amide]] group of the lysergic acid derivatives. This structure consists of [[proline]] and two other α-amino acids, linked in an unusual [[cyclol]] formation >N-C(OH)< with the carboxyl carbon of proline, at the juncture between the two [[lactam]] rings.<ref>{{cite journal| vauthors = Floss HG |title=Biosynthesis of Ergot Alkaloids and Related Compounds|journal=Tetrahedron Report|date= January 1976 |volume=32|issue=14|pages=873–912|doi=10.1016/0040-4020(76)85047-8}}</ref> Some of the important ergopeptines are summarized below.<ref>{{Cite journal| vauthors = Yates SG, Plattner RD, Garner GB |doi=10.1021/jf00064a038 |title=Detection of ergopeptine alkaloids in endophyte-infected, toxic Ky-31 tall fescue by mass spectrometry/mass spectrometry |journal=Journal of Agricultural and Food Chemistry |volume=33 |issue=4 |pages=719–722 |date = July 1985 |bibcode=1985JAFC...33..719Y |url=http://ddr.nal.usda.gov/bitstream/10113/23986/1/IND86034816.pdf }}{{dead link|date=June 2025|bot=medic}}{{cbignore|bot=medic}}</ref> In addition to the following ergopeptines, a commonly encountered term is '''ergotoxine''', which refers to a mixture of equal proportions of [[ergocristine]], [[ergocornine]] and ergocryptine, the latter being a 2:1 mixture of ''[[Ergocryptine|alpha]]''- and [[Beta-Ergocryptine|''beta''-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.”<ref>{{Cite book | vauthors = Eich E |url=https://link.springer.com/book/10.1007/978-3-540-74541-9 |title=Solanaceae and convolvulaceae - secondary metabolites: biosynthesis, chemotaxonomy, biological and economic significance: a handbook |publisher=Springer-Verlag |isbn=978-3-540-74540-2 |location=Berlin, Heidelberg |publication-date=January 12, 2008 |language=En |chapter=4.2 Ergolines |doi=10.1007/978-3-540-74541-9 |oclc=195613136 |quote = <br>“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}}</ref>

* Ergotoxine group ([[valine]] as the amino acid attached to the ergoline moiety, at R<sup>2</sup> below)
** [[Ergocristine]]
*** [[IUPAC name]]: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(phenylmethyl)-, (5'-alpha)-
*** [[CAS number]]: {{CAS|511-08-0}}
** [[Ergocornine]]
*** IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2',5'-bis(1-methylethyl)-, (5'-alpha)-
*** CAS number: {{CAS|564-36-3}}
** ''alpha''-[[Ergocryptine]]
*** IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, (5'alpha)-
*** CAS number: {{CAS|511-09-1}}
** [[beta-Ergocryptine|''beta''-Ergocryptine]]
*** IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(1-methylpropyl)-, (5'alpha(''S''))-
*** CAS number: {{CAS|20315-46-2}}
* Ergotamine group ([[alanine]] at R<sup>2</sup>)
** [[Ergotamine]]
*** IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-, (5'-alpha)-
*** CAS number: {{CAS|113-15-5}}
** [[Ergovaline]]
*** IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylethyl)-, (5'alpha)-
*** CAS number: {{CAS|2873-38-3}}
** ''alpha''-[[Ergosine]]
*** IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(2-methylpropyl)-, (5'-alpha)-
*** CAS number: {{CAS|561-94-4}}
** [[beta-Ergosine|''beta''-Ergosine]]
*** IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylpropyl)-, (5'-alpha(''S''))-
*** CAS number: {{CAS|60192-59-8}}

[[File:Ergopeptine - Ergopeptines.svg|left|Ergopeptides (structural formula)]]

{| class="wikitable" style="float:right"
|-
! Name !! R<sup>1</sup> !! R<sup>2</sup> !! R<sup>3</sup> !! Amino acid at R<sup>2</sup> !! Amino acid at R<sup>3</sup>
|-
| [[Ergocristine]] ||  || [[Isopropyl|CH(CH<sub>3</sub>)<sub>2</sub>]] || [[benzyl]] || Valine || [[Phenylalanine]]
|-
| [[Ergocornine]] ||  || CH(CH<sub>3</sub>)<sub>2</sub> || CH(CH<sub>3</sub>)<sub>2</sub> || Valine || [[Valine]]
|-
| ''alpha''-[[Ergocryptine]] ||  || CH(CH<sub>3</sub>)<sub>2</sub> || CH<sub>2</sub>CH(CH<sub>3</sub>)<sub>2</sub> || Valine || [[Leucine]]
|-
| [[beta-Ergocryptine|''beta''-Ergocryptine]] ||  || CH(CH<sub>3</sub>)<sub>2</sub> || CH(CH<sub>3</sub>)CH<sub>2</sub>CH<sub>3</sub> (''S'') || Valine || [[Isoleucine]]
|-
| [[Ergotamine]] ||  || [[Methyl|CH<sub>3</sub>]] || benzyl || [[Alanine]] || Phenylalanine
|-
| [[Ergovaline]] ||  || CH<sub>3</sub> || CH(CH<sub>3</sub>)<sub>2</sub> || Alanine || Valine
|-
| ''alpha''-[[Ergosine]] ||  || CH<sub>3</sub> || CH<sub>2</sub>CH(CH<sub>3</sub>)<sub>2</sub> || Alanine || Leucine
|-
| [[beta-Ergosine|''beta''-Ergosine]] ||  || CH<sub>3</sub> || CH(CH<sub>3</sub>)CH<sub>2</sub>CH<sub>3</sub> (''S'') || Alanine || Isoleucine
|-
| [[Bromocriptine]] ([[semisynthetic]]) || [[Bromine|Br]] || CH(CH<sub>3</sub>)<sub>2</sub> || CH<sub>2</sub>CH(CH<sub>3</sub>)<sub>2</sub> || Valine  || Leucine
|}

{{clear}}

===Clavines===
A variety of modifications to the basic ergoline are seen in nature, for example [[agroclavine]], [[elymoclavine]], [[lysergol]]. Those deriving from [[dimethylergoline]] are referred to as clavines. Examples of clavines, include [[festuclavine]], [[fumigaclavine A]], [[fumigaclavine B]] and [[fumigaclavine C]].

===Others===
Some synthetic ergoline derivatives do not fall easily into any of the above groups.  Some examples are:

* [[Cabergoline]] ([[International Nonproprietary Name|INN]])
** [[IUPAC name]]: 1-[(6-Allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea
** [[CAS number]]: {{CAS|81409-90-7}}
* [[Pergolide]] (INN)
** IUPAC name: (8β)-8-((methylthio)methyl)-6-propyl-ergoline
** CAS number: {{CAS|66104-22-1}}
* [[Lisuride]] (INN)
** IUPAC name: 3-(9,10-didehydro-6-methylergolin-8α-yl)-1,1-diethylurea
** CAS number: {{CAS|18016-80-3}}

== See also ==
* [[Ergotism]]
* [[Ergot]]
* [[LSD]]
* [[Ergine]]
* [[Migraine]]
* [[Albert Hofmann]]

== References ==
{{reflist}}

== External links ==
* [https://web.archive.org/web/20040411102155/http://www.people.vcu.edu/~asneden/The%20Ergot%20Alkaloids.pdf The Ergot Alkaloids (A. T. Sneden)]
* [https://web.archive.org/web/20040720041016/http://www.world-of-fungi.org/Mostly_Medical/Ziad_Madlom/Ergot_alkaloids.htm The Ergot Alkaloids Story (Z. Madlom)]
* [http://www.tacethno.com/info/claviceps/ergotalkfungi.txt The Psychoactive Ergot Alkaloids and their occurrence in the Microfungi&nbsp;— M. P. Bock and D. G. Parbery]
* [http://www.erowid.org/plants/mushrooms/references/other/1971_hofmann_bulletin-narcotics.shtml Hofmann, A. ''Teonanácatl and Ololiuqui, two ancient magic drugs of Mexico'' Bulletin on Narcotics 1971 1 3]
* [http://www.erowid.org/library/books_online/tihkal/tihkal26.shtml TiHKAL (A & A Shulgin) #26]

{{Ergolines}}
{{Psychedelics}}
{{Chemical classes of psychoactive drugs}}

[[Category:Tryptamine alkaloids]]
[[Category:Quinoline alkaloids]]
[[Category:Ergolines| ]]
[[Category:Alkaloids found in fungi]]