Ergoline

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Ergoline
Ergoline Structural Formulae V.1.svg
3D ergoline molecule animation.gif
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
Formula C14H16N2
Molar mass 212.296 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 Yes check.svgY
  • Key:RHGUXDUPXYFCTE-ZWNOBZJWSA-N Yes check.svgY
   (verify)

Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of these are implicated in the condition ergotism, which can take a convulsive form 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. [1]

Contents

Others, such as lysergic acid diethylamide, better known as LSD, a fully synthetic derivative, and ergine, a natural derivative found in Argyreia nervosa , Ipomoea tricolor and related species, are known psychedelic substances. [2]

Natural occurrence

Ergoline alkaloids are found in lower fungi and some species of flowering plants: the Mexican species Turbina corymbosa and Ipomoea tricolor of the Convolvulaceae (morning glory) family, the seeds of which were identified as the psychedelic plant drugs known as "ololiuhqui" and "tlitliltzin", respectively. [3] [4] The principal alkaloids in the seeds are ergine and its optical isomer isoergine, with several other lysergic acid derivatives and clavines present in lesser amounts. The Hawaiian species Argyreia nervosa includes similar alkaloids. It is possible, though not proven, that ergine or isoergine are responsible for the psychedelic effects. There may be a fungal origin of the ergoline alkaloids also in the Convolvulaceae. Like the ergot alkaloids in some monocot plants, the ergoline alkaloids found in the plant Ipomoea asarifolia (Convolvulaceae) are produced by a seed-transmitted endophytic clavicipitaceous fungus. [5]

History

Ergoline alkaloids were first isolated from ergot, a fungus that infects rye and causes ergotism or St. Anthony's fire. [6] Reports of the toxic effects due to ergoline alkaloids date back to the 12th century. [7] 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. [1] [7] 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". [1]

Attempts to characterize the activity of ergoline alkaloids began in 1907, with the isolation of ergotoxine by G. Barger and F. H. Carrin. [8] 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. [1] [8] 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. [9] 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 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. [10] 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. [7] While used to facilitate child birth, ergoline derivatives can pass into breast milk and should not be used during breastfeeding. [11] They are uterine contractors that can increase the risk of miscarriage during pregnancy. [3]

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. [12]

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. [13] 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. [13]

A famous ergoline derivative is the psychedelic drug LSD, a completely 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. [14]

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, serotonergic, and antiserotonergic. [15] 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. [15] 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. [15]

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. [15] The antagonist or agonist behavior of the ergolines are substrate dependent and mixed agonist/antagonist behaviors of ergoline derivatives have been reported. [15]

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-HT1A agonist/5-HT2A antagonist, and mesulergine, a 5-HT2A/2C antagonist. [15] 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. [15] This methodology has been used to develop selective 5-HT1A and 5-HT2A ergolines in particular.

Ergoline derivatives

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. [16]

Lysergic acid amides

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

Substituted ergine (structural formula) Ergine - Ergines.svg
Substituted ergine (structural formula)
NameR1R2R3
Ergine HHH
Ergonovine HCH(CH3)CH2OHH
Methergine HCH(CH2CH3)CH2OHH
Methysergide CH3 CH(CH2CH3)CH2OHH
LSD H CH2CH3 CH2CH3

Peptide alkaloids

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. [17] Some of the important ergopeptines are summarized below. [18] 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.

Ergopeptides (structural formula) Ergopeptine - Ergopeptines.svg
Ergopeptides (structural formula)
NameR1R2R3Amino acid at R2Amino acid at R3
Ergocristine CH(CH3)2 benzyl Valine Phenylalanine
Ergocornine CH(CH3)2CH(CH3)2Valine Valine
alpha-Ergocryptine CH(CH3)2CH2CH(CH3)2Valine Leucine
beta-Ergocryptine CH(CH3)2CH(CH3)CH2CH3 (S)Valine Isoleucine
Ergotamine CH3 benzyl Alanine Phenylalanine
Ergovaline CH3CH(CH3)2AlanineValine
alpha-Ergosine CH3CH2CH(CH3)2AlanineLeucine
beta-Ergosine CH3CH(CH3)CH2CH3 (S)AlanineIsoleucine
Bromocriptine (semisynthetic) Br CH(CH3)2CH2CH(CH3)2ValineLeucine

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:

See also

Related Research Articles

Ergine Chemical compound

Ergine, also known as d-lysergic acid amide (LSA) and d-lysergamide, is an ergoline alkaloid that occurs in various species of vines of the Convolvulaceae and some species of fungi. The psychedelic properties in the seeds of ololiuhqui, Hawaiian baby woodrose and morning glories have been linked to ergine and/or isoergine, its epimer, as it is the dominant alkaloid present in the seeds.

Lysergic acid Precursor for a range of ergoline alkaloids produced by the ergot fungus

Lysergic acid, also known as D-lysergic acid and (+)-lysergic acid, is a precursor for a wide range of ergoline alkaloids that are produced by the ergot fungus and found in the seeds of Turbina corymbosa (ololiuhqui), Argyreia nervosa, and Ipomoea tricolor. Amides of lysergic acid, lysergamides, are widely used as pharmaceuticals and as psychedelic drugs (LSD). Lysergic acid received its name as it was a product of the lysis of various ergot alkaloids.

Ergotamine Chemical compound in the ergot family of alkaloids

Ergotamine, sold under the brand names Cafergot and Ergomar among others, is an ergopeptine and part of the ergot family of alkaloids; it is structurally and biochemically closely related to ergoline. It possesses structural similarity to several neurotransmitters, and has biological activity as a vasoconstrictor.

Bromocriptine Organic Chemical Compound

Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.

Ergoloid

Ergoloid mesylates (USAN), co-dergocrine mesilate (BAN) or dihydroergotoxine mesylate, trade name Hydergine, is a mixture of the methanesulfonate salts of three dihydrogenated ergot alkaloids.

Misuse of Drugs Act (Singapore) Law of Singapore

The Misuse of Drugs Act is a drug control law in Singapore classifying substances into three categories, Classes A, B, and C. Section 44 provides that "The Minister may, by an order published in the Gazette" add, remove, or transfer drugs among the classes. The statute's penal provisions are severe by most nations' standards, providing for long terms of imprisonment, caning, and capital punishment. The law creates a presumption of trafficking for certain threshold amounts, e.g. 30 grams of cannabis. It also creates a presumption that a person possesses drugs if he possesses the keys to a premises containing the drugs, and that "Any person found in or escaping from any place or premises which is proved or presumed to be used for the purpose of smoking or administering a controlled drug shall, until the contrary is proved, be presumed to have been smoking or administering a controlled drug in that place or premises." Thus, one runs the risk of arrest for drug use by simply being in the company of drug users. The law also allows officers to search premises and individuals, without a search warrant, if he "reasonably suspects that there is to be found a controlled drug or article liable to seizure". Moreover, Section 31 allows officers to demand urinalysis of suspected drug offenders while section 8A prohibits any citizen or permanent resident of Singapore to use any prohibited drug outside of the country, and if found guilty to be punished as if they committed that act within the country.

Lysergamides

Amides of lysergic acid are collectively known as lysergamides, and include a number of compounds with potent agonist and/or antagonist activity at various serotonin and dopamine receptors.

<i>Controlled Drugs and Substances Act</i> Canadian federal drug regulation act

The Controlled Drugs and Substances Act is Canada's federal drug control statute. Passed in 1996 under Prime Minister Jean Chrétien's government, it repeals the Narcotic Control Act and Parts III and IV of the Food and Drugs Act, and establishes eight Schedules of controlled substances and two Classes of precursors. It provides that "The Governor in Council may, by order, amend any of Schedules I to VIII by adding to them or deleting from them any item or portion of an item, where the Governor in Council deems the amendment to be necessary in the public interest."

Dihydroergotamine An ergot alkaloid used to treat migraines

Dihydroergotamine (DHE), sold under the brand names D.H.E. 45 and Migranal among others, is an ergot alkaloid used to treat migraines. It is a derivative of ergotamine. It is administered as a nasal spray or injection and has an efficacy similar to that of sumatriptan. Nausea is a common side effect.

Lysergic acid hydroxyethylamide

D-Lysergic acid α-hydroxyethylamide, also known as D-lysergic acid methyl carbinolamide, is an alkaloid of the ergoline family, believed to be present in small amounts in various species in the Convolvulaceae, as well as some species of fungi.

Methylergometrine

Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and in the treatment of migraine. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.

Methysergide

Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to adverse effects. It is taken by mouth.

Lisuride

Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.

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. 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.

Nicergoline Chemical compound

Nicergoline, sold under the brand name Sermion among others, is an ergot derivative used to treat senile dementia and other disorders with vascular origins. Internationally it has been used for frontotemporal dementia as well as early onset in Lewy body dementia and Parkinson's dementia. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells. It has similar vasoactive properties in other areas of the body, particularly the lungs. Unlike many other ergolines, such as ergotamine, nicergoline is not associated with cardiac fibrosis.

Serotonin receptor agonist

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

Methylisopropyllysergamide

Methylisopropyllysergamide is an analogue of LSD that was originally discovered by Albert Hofmann at Sandoz during the original structure-activity research into LSD. It has subsequently been investigated in more detail by the team led by David E. Nichols at Purdue University. Methylisopropyllysergamide is a structural isomer of LSD, with the alkyl groups on the amide nitrogen having been subjected to a methylene shuffle. MIPLA and its ethylisopropyl homologue are the only simple N,N-dialkyl lysergamides that approach the potency of LSD itself, being around 1/3-1/2 the potency of LSD, while all other dialkyl analogues tested are only around 1/10 as potent as LSD, although some N-monoalkyl lysergamides such as the sec-butyl and t-butyl derivatives were also found to show an activity profile and potency comparable to LSD, and the mono-isopropyl derivative is only slightly weaker than MIPLA. Apart from its lower potency, the hallucinogenic effects of methylisopropyllysergamide are similar to those of LSD itself, and the main use for this drug has been in studies of the binding site at the 5-HT2A receptor through which LSD exerts most of its pharmacological effects.

Ergocryptine

Ergocryptine is an ergopeptine and one of the ergot alkaloids. It is isolated from ergot or fermentation broth and it serves as starting material for the production of bromocriptine.

LSD-Pip Compound related to LSD

LSD-Pip is a compound from the ergoline family, related to LSD but with the N,N-diethyl substitution replaced by a piperidine group. It is more potent than the corresponding pyrrolidine and morpholine analogues, but is still several times less potent than LSD as a 5-HT2A agonist. Early studies suggested this compound to be inactive as a psychedelic in humans, though this does not seem to have been confirmed by any more recent work.

References

  1. 1 2 3 4 Schiff, Paul L. (September 2006). "Ergot and Its Alkaloids". American Journal of Pharmaceutical Education. 70 (5): 98. doi:10.5688/aj700598. ISSN   0002-9459. PMC   1637017 . PMID   17149427.
  2. ↑ 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". J Psychoactive Drugs. 45 (1): 79–93. doi:10.1080/02791072.2013.763570. PMID   23662334. S2CID   22086799.
  3. 1 2 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.
  4. ↑ Carod-Artal, FJ (2015). "Hallucinogenic drugs in pre-Columbian Mesoamerican cultures". Neurologia. 30 (1): 42–9. doi: 10.1016/j.nrl.2011.07.003 . PMID   21893367.
  5. ↑ Steiner, U; Ahimsa-Müller, MA; Markert, A; Kucht, S; Groß, J; Kauf, N; Kuzma, M; Zych, M; Lamshöft, M; Furmanowa, M; Knoop, V; Drewke, C; Leistner, E (2006). "Molecular characterization of a seed transmitted clavicipitaceous fungus occurring on dicotyledoneous plants (Convolvulaceae)". Planta. 224 (3): 533–44. doi:10.1007/s00425-006-0241-0. PMID   16525783. S2CID   25682792.
  6. ↑ Gerhards, Nina; Neubauer, Lisa; Tudzynski, Paul; Li, Shu-Ming (2014-12-10). "Biosynthetic Pathways of Ergot Alkaloids". Toxins. 6 (12): 3281–3295. doi: 10.3390/toxins6123281 . ISSN   2072-6651. PMC   4280535 . PMID   25513893.
  7. 1 2 3 N.J.A. de Groot, Akosua; van Dongen, Pieter W.J.; Vree, Tom B.; Hekster, Yechiel A.; van Roosmalen, Jos (1998). "Ergot Alkaloids". Drugs. 56 (4): 523–535. doi:10.2165/00003495-199856040-00002. ISSN   0012-6667. PMID   9806101. S2CID   46971443.
  8. 1 2 Sfetcu, Nicolae (2014). Health & Drugs - Disease, Prescription & Medication. Lulu.com. ISBN   9781312039995.
  9. ↑ Stoll, A.; Hofmann, A. (1965), "Chapter 21 The Ergot Alkaloids", The Alkaloids: Chemistry and Physiology, Elsevier, vol. 8, pp. 725–783, doi:10.1016/s1876-0813(08)60060-3, ISBN   978-0-12-469508-5
  10. ↑ 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.
  11. ↑ kidsgrowth.org --> Drugs and Other Substances in Breast Milk Archived 2007-06-23 at archive.today Retrieved on June 19, 2009.
  12. ↑ Winkelman, Michael. Roberts, Thomas B. (2007). Psychedelic medicine : new evidence for hallucinogenic substances as treatments. Praeger Publishers. ISBN   978-0-275-99023-7. OCLC   85813998.{{cite book}}: CS1 maint: multiple names: authors list (link)
  13. 1 2 Lataste, X. (February 1984). "The History and Pharmacology of Dopamine Agonists". Canadian Journal of Neurological Sciences. 11 (S1): 118–123. doi: 10.1017/S0317167100046266 . ISSN   0317-1671. PMID   6713309.
  14. ↑ http://www.incb.org/pdf/e/list/red.pdf Archived 2008-02-27 at the Wayback Machine .
  15. 1 2 3 4 5 6 7 Mantegani, Sergio; Brambilla, Enzo; Varasi, Mario (May 1999). "Ergoline derivatives: receptor affinity and selectivity". Il Farmaco. 54 (5): 288–296. doi:10.1016/s0014-827x(99)00028-2. ISSN   0014-827X. PMID   10418123.
  16. ↑ 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.
  17. ↑ G. Floss, Heinz (1976). "Biosynthesis of Ergot Alkaloids and Related Compounds". Tetrahedron Report. 32 (14): 873–912. doi:10.1016/0040-4020(76)85047-8.
  18. ↑ Yates, S. G.; Plattner, R. D.; Garner, G. B. (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. doi:10.1021/jf00064a038.[ permanent dead link ]
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