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Ergoline

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Title: Ergoline  
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Subject: Ergotamine, Pergolide, Methysergide, Cabergoline, LSM-775
Collection: Alkaloids, Alkaloids Found in Fungi, Ergolines
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Ergoline

Ergoline
Systematic (IUPAC) name
(6aR)-4,6,6a,7,8,9,10,10a-Octahydroindolo[4,3-fg]quinoline
Identifiers
CAS Registry Number  Y
ATC code None
PubChem CID:
ChemSpider  Y
ChEBI  Y
Chemical data
Formula C14H16N2
Molecular mass 212.29g/mol
 Y   

Ergoline is a chemical compound whose structural skeleton is contained in a diverse range of alkaloids. Ergoline derivatives are used clinically for the purpose of vasoconstriction (5-HT1 receptor agonists—ergotamine) and in the treatment and alleviation of migraines (used with caffeine) and Parkinson's disease. Some ergoline alkaloids found in ergot fungi are implicated in the condition ergotism, which causes convulsive and gangrenous symptoms. Others include psychedelic (Psychoactive substance) (e.g., LSD, lysergic acid and some alkaloids in Ipomoea tricolor and related species ).

Contents

  • Uses 1
  • Natural occurrence 2
  • History 3
  • Ergoline derivatives 4
    • Lysergic acid amides 4.1
    • Peptide alkaloids 4.2
    • Clavines 4.3
    • Others 4.4
  • See also 5
  • References 6
  • External links 7

Uses

In addition to the naturally occurring ergonovine (used as an oxytocic) and ergotamine (a vasoconstrictor used to control migraine), synthetic derivatives of importance are the oxytocic methergine, the anti-migraine drugs dihydroergotamine and methysergide, hydergine (a mixture of dihydroergotoxine mesylates, INN: ergoline mesylates), and bromocriptine, used for numerous purposes including treatment of Parkinson's disease. Newer synthetic ergolines used for Parkinson's disease include pergolide and lisuride.

Perhaps the most famous ergoline derivative is the [1]

Ergolines can pass into breast milk and should not be used during breastfeeding.[2] They are uterine contractors that can increase the risk of miscarriage during pregnancy.[3]

Natural occurrence

Ergoline alkaloids are found in lower fungi[3] and two species of flowering plants: the Mexican species Rivea corymbosa and Ipomoea violacea of the Convolvulaceae (morning glory) family, the seeds of which were identified as the psychedelic plant drugs known as "ololiuhqui" and "tlitliltzin". 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 epiphytic clavicipitaceous fungus.[4]

History

Ergoline alkaloids were first isolated from ergot, a fungus that infects grain and causes the disease ergotism. Ergot also has a long history of medicinal use, which led to attempts to characterize its activity chemically. This began in 1906 with the isolation by G. Barger and F. H. Carr of ergotoxine, so-named since it appeared to exhibit more of the toxicity of ergot than its therapeutic qualities. With the isolation of ergotamine in 1918 by Arthur Stoll came the first therapeutic use of isolated ergoline alkaloids.

With the determination of the basic chemical structure of the ergot alkaloids in the early 1930s, an era of intensive exploration of synthetic derivatives began.

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.[3]

Lysergic acid amides

  • 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)
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

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 comprises 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.[5] Some of the important ergopeptines are summarized below.[6] 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.

  • Ergotoxine group (valine as the amino acid attached to the ergoline moiety, at R2 below)
    • Ergocristine
      • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(phenylmethyl)-, (5'-alpha)-
      • CAS number: 511-08-0
    • 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)
Name R1 R2 R3 Amino acid at R3
Ergocristine CH(CH3)2 benzyl Phenylalanine
Ergocornine CH(CH3)2 CH(CH3)2 Valine
alpha-Ergocryptine CH(CH3)2 CH2CH(CH3)2 Leucine
beta-Ergocryptine CH(CH3)2 CH(CH3)CH2CH3 (S) Isoleucine
Ergotamine CH3 benzyl Phenylalanine
Ergovaline CH3 CH(CH3)2 Valine
alpha-Ergosine CH3 CH2CH(CH3)2 Leucine
beta-Ergosine CH3 CH(CH3)CH2CH3 (S) Isoleucine
Bromocriptine (semisynthetic) Br CH(CH3)2 CH2CH(CH3)2 Leucine


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 C.

Others

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

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

See also

References

  1. ^ http://www.incb.org/pdf/e/list/red.pdf.
  2. ^ kidsgrowth.org --> Drugs and Other Substances in Breast Milk Retrieved on June 19, 2009.
  3. ^ a b c Schardl CL, Panaccione DG, Tudzynski P (2006). "Ergot alkaloids – biology and molecular biology". The Alkaloids: Chemistry and Biology. The Alkaloids: Chemistry and Biology 63: 45–86.  
  4. ^ 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.  
  5. ^ G. Floss, Heinz (1976). "Biosynthesis of Ergot Alkaloids and Related Compounds". Tetrahedron Report 32 (14): 873 to 912.  
  6. ^ 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.  

External links

  • The Ergot Alkaloids (A. T. Sneden)
  • The Ergot Alkaloids Story (Z. Madlom)
  • The Psychoactive Ergot Alkaloids and their occurrence in the Microfungi — M. P. Bock and D. G. Parbery
  • Bulletin on Narcotics 1971 1 3Teonanácatl and Ololiuqui, two ancient magic drugs of MexicoHofmann, A.
  • TiHKAL (A & A Shulgin) #26
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