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Ergoline

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Ergoline
Clinical data
ATC code
  • none
Identifiers
  • (6aR)-4,6,6a,7,8,9,10,10a-Octahydroindolo[4,3-fg]quinoline
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H16N2
Molar mass212.296 g·mol−1
3D model (JSmol)
  • [H][C@@]34Cc1c[nH]c2cccc(c12)[C@@]3([H])CCCN4
  • InChI=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 checkY
  • Key:RHGUXDUPXYFCTE-ZWNOBZJWSA-N checkY
  (verify)

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[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 of lysergic acid, used primarily in the manufacture of semi-synthetic derivatives.[2]

Others, such as lysergic acid diethylamide, better known as LSD, a semi-synthetic derivative, and ergine, a natural derivative found in Argyreia nervosa, Ipomoea tricolor and related species, are known psychedelic substances.[3]

Natural occurrence

[edit]

Ergoline alkaloids are found in fungi 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 and Ipomoea 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 as ololiuhqui[9][10]) The principal alkaloids in the seeds appear to be ergine and isoergine, but they're just decomposition products of lysergic 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 are ergine, ergonovine, and lysergol, with lysergol showing the weakest effect[20] (refs: Ergine / Psychedelic Effects, Ergometrine / Psychedelic Effects).

History

[edit]

Ergoline alkaloids were first isolated from ergot, a fungus that infects rye and causes ergotism 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, 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.[2][23] 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.[24] Though the synthesis found no industrial application, this was a huge leap forward in the industry.

Uses

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There are a variety of clinically useful ergoline derivatives for the purpose of vasoconstriction, the treatment of migraines, 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.[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 to ergonovine, an ergoline derivative found in ergot, which is a powerful oxytocic. From this, methergine, a synthetic derivative, was elucidated.[22] While used to facilitate child birth, ergoline derivatives can pass into breast 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 is ergotamine, an alkaloid also found in ergot. It acts as a vasoconstrictor and has been reported to control migraines. From ergotamine, the anti-migraine drugs dihydroergotamine and methysergide were developed by Albert Hofmann.[27]

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.[28] 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.[28]

A famous ergoline derivative is the psychedelic drug LSD, a 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.[29]

Mechanism of action

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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, serotonergic, and antiserotonergic.[30] Ergoline alkaloids often interfere with multiple receptor sites, leading to negative side effects and adding to the challenge of drug development.

Dopaminergic/antidopaminergic

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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.[30] Drugs such as bromocriptine 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 in antiemetics and in the treatment of schizophrenia. These substances are neuroleptic 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]

Serotonergic/antiserotonergic

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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-HT1A agonist/5-HT2A antagonist, and mesulergine, 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.

Ergoline derivatives

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There are 3 main classes of ergoline derivatives, the water-soluble amides of lysergic acid, the water-insoluble ergopeptines (i.e., ergopeptides), and the clavine group.[31]

Lysergic acid amides

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Main article: Lysergamides
  • Ergine (LSA, D-lysergic acid amide, LAA, LA-111)
  • Ergonovine (ergobasine)
    • INN: ergometrine
    • IUPAC name: (8beta(S))-9,10-didehydro-N-(2-hydroxy-1-methylethyl)-6-methyl-ergoline-8-carboxamide
    • CAS number: 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: 113-42-8
  • Methysergide (UML-491)
    • INN: methysergide
    • IUPAC name: (8beta)-9,10-didehydro-N-(1-(hydroxymethyl)propyl)-1,6-dimethyl-ergoline-8-carboxamide
    • CAS number: 361-37-5
  • LSD (D-lysergic acid diethylamide, LSD-25)
    • INN: lysergide
    • IUPAC name: (8beta)-9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-carboxamide
    • CAS number: 50-37-3
  • LSH (D-lysergic acid α-hydroxyethylamide)
    • IUPAC name: 9,10-didehydro-N-(1-hydroxyethyl)-6-methylergoline-8-carboxamide
    • CAS number: 3343-15-5

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

Substituted ergine (structural formula)
Substituted ergine (structural formula)
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 alkaloids

[edit]

Peptide ergot alkaloids or ergopeptines (also known as ergopeptides) are ergoline derivatives that contain a tripeptide 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.[32] Some of the important ergopeptines are summarized below.[33] 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 alpha- and 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.”[34]

  • Ergotoxine group (valine as the amino acid attached to the ergoline moiety, at R2 below)
    • Ergocristine
    • Ergocornine
      • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2',5'-bis(1-methylethyl)-, (5'-alpha)-
      • CAS number: 564-36-3
    • alpha-Ergocryptine
      • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, (5'alpha)-
      • CAS number: 511-09-1
    • beta-Ergocryptine
      • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(1-methylpropyl)-, (5'alpha(S))-
      • CAS number: 20315-46-2
  • Ergotamine group (alanine at R2)
    • Ergotamine
      • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-, (5'-alpha)-
      • CAS number: 113-15-5
    • Ergovaline
      • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylethyl)-, (5'alpha)-
      • CAS number: 2873-38-3
    • alpha-Ergosine
      • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(2-methylpropyl)-, (5'-alpha)-
      • CAS number: 561-94-4
    • beta-Ergosine
      • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylpropyl)-, (5'-alpha(S))-
      • CAS number: 60192-59-8
Ergopeptides (structural formula)
Ergopeptides (structural formula)
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

Clavines

[edit]

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

[edit]

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

See also

[edit]

References

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  1. ^ Schardl CL, Panaccione DG, Tudzynski P (2006). "Ergot alkaloids--biology and molecular biology". The Alkaloids. Chemistry and Biology. 63. Elsevier: 45–86. doi:10.1016/s1099-4831(06)63002-2. ISBN 978-0-12-469563-4. PMID 17133714.
    "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)."
    II. Through the Ages: A History of Ergot Alkaloid Use, Abuse, and Poisoning, p. 50
  2. ^ a b c d Schiff PL (October 2006). "Ergot and its alkaloids". American Journal of Pharmaceutical Education. 70 (5): 98. doi:10.5688/aj700598. PMC 1637017. PMID 17149427.
  3. ^ Juszczak GR, Swiergiel AH (2013). "Recreational use of D-lysergamide from the seeds of Argyreia nervosa, Ipomoea tricolor, Ipomoea violacea, and Ipomoea purpurea in Poland". Journal of Psychoactive Drugs. 45 (1): 79–93. doi:10.1080/02791072.2013.763570. PMID 23662334. S2CID 22086799.
  4. ^ Schultes R (1973). "4. Plants of Hallucinogenic Use / The Fungi". The Botany and Chemistry of Hallucinogens. Springfield, IL: Charles Thomas. p. 37. ISBN 9780398064167.
    "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
  5. ^ Wasson RG, Hofmann A, Ruck CA, Webster P (November 25, 2008) [1978]. Forte R (ed.). The Road to Eleusis: Unveiling the Secret of the Mysteries (30th Anniversary ed.). Berkeley, Calif.: North Atlantic Books. ISBN 978-1-55643-752-6.
    "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
  6. ^ Leistner E, Steiner U (February 3, 2018). "The Genus Periglandula and Its Symbiotum with Morning Glory Plants (Convolvulaceae)". In Anke T, Schüffler A (eds.). Physiology and Genetics. Cham: Springer International Publishing. pp. 131–147. doi:10.1007/978-3-319-71740-1_5. ISBN 978-3-319-71739-5. Retrieved 2024-11-21.
  7. ^ Nowak J, Woźniakiewicz M, Klepacki P, Sowa A, Kościelniak P (May 2016). "Identification and determination of ergot alkaloids in Morning Glory cultivars". Analytical and Bioanalytical Chemistry. 408 (12): 3093–3102. doi:10.1007/s00216-016-9322-5. PMC 4830885. PMID 26873205.
    "ergine and ergometrine concentration is 12-fold lower in plant samples than in seeds." Analysis of IP-HB2 young plants
  8. ^ Ruck CA (2006). Sacred Mushrooms of the Goddess: The Secrets of Eleusis. Berkeley, California: Ronin Publishing, Inc. ISBN 978-1-57951-030-5.
    "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)
  9. ^ a b Schardl CL, Panaccione DG, Tudzynski P (2006). Ergot alkaloids – biology and molecular biology. The Alkaloids: Chemistry and Biology. Vol. 63. pp. 45–86. doi:10.1016/S1099-4831(06)63002-2. ISBN 978-0-12-469563-4. PMID 17133714.
  10. ^ Carod-Artal FJ (2015). "Hallucinogenic drugs in pre-Columbian Mesoamerican cultures". Neurologia. 30 (1): 42–49. doi:10.1016/j.nrl.2011.07.003. PMID 21893367.
  11. ^ Shulgin A (2012-12-02) [1976]. "4. Psychotomimetic Agents". In Maxwell G (ed.). Psychopharmacological agents. Medicinal Chemistry. Vol. 4. New York: Academic Press. pp. 71–72. ISBN 978-0-12-290559-9.
    "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)
  12. ^ Schultes RE, Hofmann A (1973). The Botany and Chemistry of Hallucinogens. Springfield, IL: Charles Thomas. p. 246. ISBN 9780398064167.
    "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
  13. ^ Flieger M, Sedmera P, Vokoun J, R̆ic̄icovā A, R̆ehác̆ek Z (1982-02-19). "Separation of four isomers of lysergic acid α-hydroxyethylamide by liquid chromatography and their spectroscopic identification". Journal of Chromatography A. 236 (2): 441–452. doi:10.1016/S0021-9673(00)84895-5. ISSN 0021-9673.
  14. ^ Ramstad E (1968). "Chemistry of alkaloid formation in ergot". Lloydia. 31: 327–341.
  15. ^ Kleinerová E, Kybal J (September 1973). "Ergot alkaloids. IV. Contribution to the biosynthesis of lysergic acid amides". Folia Microbiologica. 18 (5): 390–392. doi:10.1007/BF02875934. PMID 4757982.
  16. ^ Panaccione DG, Tapper BA, Lane GA, Davies E, Fraser K (October 2003). "Biochemical outcome of blocking the ergot alkaloid pathway of a grass endophyte". Journal of Agricultural and Food Chemistry. 51 (22): 6429–6437. doi:10.1021/jf0346859. PMID 14558758.
  17. ^ Panaccione DG (2010). "Ergot alkaloids". In Hofrichter M (ed.). The Mycota, Industrial Applications. Vol. 10 (2nd ed.). Berlin-Heidelburg, Germany: Springer-Verlag. pp. 195–214.
  18. ^ Nowak J, Woźniakiewicz M, Klepacki P, Sowa A, Kościelniak P (May 2016). "Identification and determination of ergot alkaloids in Morning Glory cultivars". Analytical and Bioanalytical Chemistry. 408 (12) (published February 14, 2016): 3093–3102. doi:10.1007/s00216-016-9322-5. PMC 4830885. PMID 26873205.
    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.
  19. ^ Eich E (January 12, 2008). "4.2 Ergolines". Solanaceae and convolvulaceae - secondary metabolites: biosynthesis, chemotaxonomy, biological and economic significance: a handbook. Berlin, Heidelberg: Springer-Verlag. doi:10.1007/978-3-540-74541-9. ISBN 978-3-540-74540-2. OCLC 195613136.
    Table 4.1 Unambiguously ergoline-positive Ipomoea species (pages 225-227)
    Table 4.4 Unambiguously ergoline-positive Argyreia species (p. 236)
    Table 4.5 Unambiguously ergoline-positive Stictocardia and Turbina species (p. 238)
  20. ^ Heim E, Heimann H, Lukács G (1968). "Die psychische Wirkung der mexikanischen Droge "Ololiuqui" am Menschen". Psychopharmacologia (in German). 13 (1): 35–48. doi:10.1007/BF00401617. PMID 5675457
    c) ᴅ-Lysergol

    “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
    Translated from German with ChatGPT.    {{cite journal}}: CS1 maint: postscript (link)
  21. ^ Gerhards N, Neubauer L, Tudzynski P, Li SM (December 2014). "Biosynthetic pathways of ergot alkaloids". Toxins. 6 (12): 3281–3295. doi:10.3390/toxins6123281. PMC 4280535. PMID 25513893.
  22. ^ a b c de Groot AN, van Dongen PW, Vree TB, Hekster YA, van Roosmalen J (October 1998). "Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology". Drugs. 56 (4): 523–535. doi:10.2165/00003495-199856040-00002. PMID 9806101. S2CID 46971443.
  23. ^ a b Sfetcu N (2014). Health & Drugs - Disease, Prescription & Medication. Lulu.com. ISBN 9781312039995.
  24. ^ Stoll A, Hofmann A (1965). "Chapter 21 The Ergot Alkaloids". The Alkaloids: Chemistry and Physiology. Vol. 8. Elsevier. pp. 725–783. doi:10.1016/s1876-0813(08)60060-3. ISBN 978-0-12-469508-5.
  25. ^ European Commission. Joint Research Centre. Report on the 2017 proficiency test of the European Union reference laboratory for mycotoxins determination of ergot alkaloids in rye. OCLC 1060942360.
  26. ^ kidsgrowth.org --> Drugs and Other Substances in Breast Milk Archived 2007-06-23 at archive.today Retrieved on June 19, 2009.
  27. ^ Winkelman M, Roberts TB (2007). Psychedelic medicine : new evidence for hallucinogenic substances as treatments. Praeger Publishers. ISBN 978-0-275-99023-7. OCLC 85813998.
  28. ^ a b Lataste X (February 1984). "The history and pharmacology of dopamine agonists". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques. 11 (1 Suppl): 118–123. doi:10.1017/S0317167100046266. PMID 6713309.
  29. ^ "List of Precursors and Chemicals Frequently Used in the Illicit Manufacture of Narcotic Drugs and Psychotropic Substances Under International Control" (PDF). International Narcotics Control Board (Eleventh ed.). Vienna, Austria. January 2007. Archived from the original (PDF) on 2008-02-27..
  30. ^ a b c d e f g Mantegani S, Brambilla E, Varasi M (May 1999). "Ergoline derivatives: receptor affinity and selectivity". Farmaco. 54 (5): 288–296. doi:10.1016/s0014-827x(99)00028-2. PMID 10418123.
  31. ^ Schardl CL, Panaccione DG, Tudzynski P (2006). Ergot alkaloids – biology and molecular biology. The Alkaloids: Chemistry and Biology. Vol. 63. pp. 45–86. doi:10.1016/S1099-4831(06)63002-2. ISBN 978-0-12-469563-4. PMID 17133714.
  32. ^ Floss HG (January 1976). "Biosynthesis of Ergot Alkaloids and Related Compounds". Tetrahedron Report. 32 (14): 873–912. doi:10.1016/0040-4020(76)85047-8.
  33. ^ Yates SG, Plattner RD, Garner GB (July 1985). "Detection of ergopeptine alkaloids in endophyte-infected, toxic Ky-31 tall fescue by mass spectrometry/mass spectrometry" (PDF). Journal of Agricultural and Food Chemistry. 33 (4): 719–722. doi:10.1021/jf00064a038.[permanent dead link‍]
  34. ^ Eich E (January 12, 2008). "4.2 Ergolines". Solanaceae and convolvulaceae - secondary metabolites: biosynthesis, chemotaxonomy, biological and economic significance: a handbook. Berlin, Heidelberg: Springer-Verlag. doi:10.1007/978-3-540-74541-9. ISBN 978-3-540-74540-2. OCLC 195613136.
    "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
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