Ergot alkaloids

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Ears of rye with ergot

As ergot alkaloids ( ergot alkaloids , Secalealkaloide ) 80 naturally occurring, about organic compounds from the group of indole alkaloids , respectively. They are mainly found in ergot , the sclerotia of the ergot fungus Claviceps purpurea , which grows as a parasite on rye and other sweet grasses . Ergot alkaloids are also produced by other organisms, in particular sac fungi of the genera Claviceps , Neotyphodium , Epichloë , Balansia , Periglandula and Aspergillus and Penicillium . These toxic for the most part alkaloids were the cause of the as ergotism designated epidemic like , poisonings from early medieval to the end of the 20th century occurred. Since the 18th century, naturally occurring ergot alkaloids, later partially synthetic derivatives, have been used as medicinal substances and are currently used as building blocks for various synthetic drugs .

history

While no poisoning by ergot alkaloids is known from antiquity, when wheat was predominantly grown, the first documented, epidemic-like case of ergotism occurred in 857 at Xanten . 922 are said to have fallen victim to an ergot epidemic across Europe - mainly in France and Spain - around 40,000 people. In 1582, Lonicerus named ergot ( Secale cornutum ) as a medicine in his “herb book” ; Since the 17th century the drug has been used in gynecological practice in Germany to stop bleeding after childbirth. Despite clear indications of a connection between the use of ergot-containing flour and the occurrence of ergotism, legislative measures were only taken in Europe after new epidemics in 1770 and 1777. In the USA, the first publication on the use of ergot in labor induction appeared in 1808.

After the development cycle of the ergot fungus Claviceps purpurea had been elucidated and described by the mycologist Edmond Tulasne around 1853 , Charles Tanret extracted a substance from ergot - albeit quite contaminated - which he called "ergotinine". Just like the "ergotoxin", which was discovered in 1907, it is a mixture of different ergot alkaloids. It was not until Arthur Stoll that ergotamine was used to isolate the first pure ergot alkaloid in 1918 .

Albert Hofmann (2006)

With this discovery, lysergic acid could be identified as the basic structure underlying most ergot alkaloids. The remaining alkaloids of ergot were discovered over the next 25 years:

  • Ergotamine group: Ergotamine / Ergotamine (1918), Ergosin / Ergosinine (1936)
  • Ergometrin group: Ergometrin (Ergobasin, Ergonovin) / Ergometrinin (1935)
  • Ergotoxin group: Ergokristin / Ergokristinin (1935), Ergokryptin / Ergokryptinin (1937), Ergocornin / Ergocorninin (1943), Ergostin / Ergostinin (1943)

Special contributions to the study of ergot alkaloids has the Swiss chemist Albert Hofmann purchased, whose research 1943 for accidental discovery of the psychedelic effective hallucinogen LSD led (lysergic acid diethylamide).

Molecular structure

Structural formula of ergoline

The tetracyclic ergoline is characteristic of the chemical structure of ergot alkaloids . The ergolines found in nature are methylated on the nitrogen in position 6 of the ergoline system and have further substituents in particular in position 8 . The ergoline skeleton of the majority of ergot alkaloids also has a double bond between C9 and C10 . Based on their substitution pattern, ergot alkaloids can be divided into four groups:

  • Clavins
  • Lysergic acids
  • simple lysergic acid amides and
  • Peptide alkaloids.

Clavins

Clavins, such as B. Lysergol , in contrast to all other naturally occurring ergolines, are not derived from lysergic acid, but from its precursors with a lower oxidation level (e.g. alcohols ).

The ergot contains the clavins Agroclavin, Elymoclavin, Molliclavin, Lysergin, Lysergol, Lysergen, Setoclavin, Isosetoclavin, Penniclavin, Isopenniclavin, Festuclavin, Pyroclavin, Costaclavin and Fumigaclavin A u. B. Likewise, so-called Secoergoline without a complete Ergoline structure, such. B. chanoclavine, can be detected. They are biogenetic precursors of the clavins.

Lysergic acids

Lysergic acids, such as B. lysergic acid and paspalsic acid are end products or simple intermediate products in the biosynthesis of higher ergot alkaloids.

Simple lysergic acid amides

General structural formula of the lysergic acid amides

Simple lysergic acid amides, such as. B. Ergometrine , are formed by the ergot fungus through the condensation of lysergic acid and an amino acid (e.g. alanine ). Other simple lysergic acid amides, such as. B. Ergin (lysergic acid amide) are degradation products of higher ergot alkaloids.

Surname Substituent R 1 Substituent R 2 Substituent R 3
Ergin -H -H -H
LSH -H -CH 3 CHOH -H
Ergometrist -H -CH (CH 3 ) CH 2 OH -H
Methylergometrine * -H -CH (CH 2 CH 3 ) CH 2 OH -H
Methysergide * -CH 3 -CH (CH 2 CH 3 ) CH 2 OH -H
LSD * -H -CH 2 CH 3 -CH 2 CH 3
ALD-52 * -C (O) CH 3 -CH 2 CH 3 -CH 2 CH 3
1P-LSD * -C (O) CH 2 CH 3 -CH 2 CH 3 -CH 2 CH 3
1CP-LSD * -C (O) C 3 H 5 -CH 2 CH 3 -CH 2 CH 3
1B-LSD * -C (O) CH 2 CH 2 CH 3 -CH 2 CH 3 -CH 2 CH 3

* Methylergometrine, methysergide, LSD, ALD-52, 1P-LSD, 1CP-LSD and 1B-LSD are not ergot alkaloids in the true sense, but rather partly synthetically produced derivatives of these.

Peptide alkaloids

Peptide alkaloids are condensation products of lysergic acid and a usually tricyclic tripeptide . One distinguishes between:

  • Ergopeptins and
  • Ergopeptamen

The ergopeptins are divided according to the amino acid directly bound to the D-lysergic acid into representatives of:

  • Ergotamine group (first amino acid here is L-alanine , e.g .: ergotamine, ergovalin, α-ergosine, β-ergosine)
  • Ergotoxin group (first amino acid here is L-valine , e.g .: Ergocristine, Ergocornine, α-Ergocryptine, β-Ergocryptine)
  • Ergoxin group (first amino acid here is α-aminobutyric acid , e.g .: Ergostin, Ergonin, α-Ergoptin, β-Ergoptin)
General structural formula of the Ergopeptins

Ergopeptins are the most diverse group of ergot alkaloids. The best-known representative is ergotamine , the main alkaloid of ergot. Furthermore, the ergopeptins ergocornine, ergocristine, α-ergocryptine, β-ergocryptine, ergovalin, α-ergosine and β-ergosine could be identified as constituents of the ergot. Ergovaline is a main alkaloid of the Neotyphodium and Epichloë species growing endophytically in pasture grasses and of veterinary-toxicological importance ( Fescue toxicosis ). 9,10-dihydroergopeptins are very rare in nature and have so far only been detected in Sphacelia sorghi and Claviceps africana . Partially synthetically obtained dihydroergopeptins, such as. B. Dihydroergotamine and Dihydroergotoxin , have a therapeutic value in the treatment of migraine and cardiovascular diseases.

Ergopeptin Substituent R 2 (pos. 2 ′) Substituent R 3 (pos. 5 ′)
Ergotamine CH 3 CH 2 C 6 H 5
Ergovalin CH 3 CH (CH 3 ) 2
α-ergosine CH 3 CH 2 CH (CH 3 ) 2
β-ergosine CH 3 CH (CH 3 ) (C 2 H 5 )
Ergocristine CH (CH 3 ) 2 CH 2 C 6 H 5
Ergocornine CH (CH 3 ) 2 CH (CH 3 ) 2
α-ergocryptine CH (CH 3 ) 2 CH 2 CH (CH 3 ) 2
β-ergocryptine CH (CH 3 ) 2 CH (CH 3 ) (C 2 H 5 )

In ergopeptams, the oxazolid ring of the first amino acid is open (between 1 'and 2').

Partially synthetic modifications

Numerous modified ergolines were developed based on the naturally occurring ergot alkaloids. The previously used migraine prophylactic agent methysergide is derived from the simple lysergic acid amide ergometrine. Dihydroergotamine , which is also used in migraine therapy, is obtained from ergotamine by hydrogenation. Isoergolines ( suffix : -inine, e.g. ergotamine) differ stereochemically from ergolines by an α-position substituent in position 8 of the ergoline skeleton. Isoergolines are formed from ergolines through isomerization reactions in aqueous solution. They are mostly degradation products or processing artifacts in the isolation of ergot alkaloids. As a rule, they have a lower pharmacological activity. In contrast, some partially synthetic isoergolines such. B. Lisurid and Tergurid , highly potent drugs in the therapy of Parkinson's disease .

Occurrence

Ears of rye with ergot

The most important producers of ergot alkaloids are the ergot fungi from the Clavicipitaceae family . In addition to Claviceps purpurea , Claviceps paspali , Claviceps fusiformis, these include representatives of the genera Balansia and Epichloë / Neotyphodium . These fungi live as epibionts and endophytes on more than 600 plant species belonging to the sweet grass , rush and sour grass families . Many members of the Balansia genus selectively produce clavine alkaloids. The spectrum of ergot alkaloids produced by claviceps and epichloë / neotyphodium is more extensive. In grasses that have been attacked by Neotyphodium coenophialum , the ergopeptin ergovalin can also be detected in addition to simple ergot alkaloids. Claviceps purpurea prefers to grow on rye , but it can also parasitize on other cereal and wild grass species. The content of ergot alkaloids in its sclerotium, ergot, is between about 0.2–1% of the dry matter and includes all four groups of this substance class. Other producers of ergot alkaloids are sac fungi of the genera Penicillium and Aspergillus .

Sky-blue morning glory

Ergot alkaloids, from clavins to simple ergopeptins, could also be detected in various representatives of the bindweed family , such as the sky-blue morning glory . Here they are considered to be a cause of their psychotropic properties and toxicity. For the occurrence of ergot alkaloids in bindweed plants, an infestation with ergot fungi has been discussed. Ergot fungi of the previously unknown genus Periglandula were identified as producers of these alkaloids in bindweed plants .

Occasional occurrences of clavins in other departments of the mushrooms , including the yoke and stand mushrooms , have also been reported.

Medical use

Because of their pharmacodynamic effects, some ergot alkaloids are used in medicine and the like. a. for the treatment of migraines , peripheral circulatory disorders, Parkinson's disease and restless legs syndrome or are used as contractions and antihypertensive drugs . They are also used in veterinary medicine .

Pharmacological properties

The effects of ergot alkaloids are diverse. They can stimulate the dopamine receptors and inhibit the release of prolactin and somatotropin . They are partial agonists on the serotonin receptors . They have a contracting effect on the uterine muscles (esp. Ergometrine); The name "ergot" goes back to this long-known effect. Natural ergotamine in particular has a vasoconstrictor effect. The hydrogenated ergotamines block the α- adrenoreceptors , which under certain circumstances can dilate contracted vessels .

Indication and preparations

Ergot alkaloids

Derivatives of ergot alkaloids

Legal

The German Basic Substance Monitoring Act restricts the supply of ergotamine: it could be used as a basis for the production of LSD , a narcotic drug that is banned in Germany . Together with Ergometrin, it also falls under the "United Nations Convention on December 20, 1988 against the illicit traffic in narcotic drugs and psychotropic substances ( Narcotics Convention )" .

literature

  • Albert Hofmann: The ergot alkaloids. From ergot to LSD. The chemistry of ergot alkaloids. Nachtschatten, o. O. 2000 (reprint from 1964), ISBN 3-907080-64-5 .
  • Otto Kraupp, Fred Lembeck (ed.): Ergot alkaloids today. Therapeutic consequences of a chemical-pharmacological differentiation in the light of new research results. Thieme, Stuttgart 1982, ISBN 3-13-621001-8 .
  • Claudia Arntz: Molecular biological studies on alkaloid synthesis in the claviceps. Cramer, Berlin a. a. 1999.
  • Julia Groß: Studies on the occurrence of ergolines in higher plants of the Convolvulaceae family and in endophytic fungi. Diss. Bonn 2004.
  • Andrea Sinz: The importance of ergot alkaloids as medicinal substances. Pharmacy in our time 37 (4), pp. 306-309 (2008), doi : 10.1002 / pauz.200700273
  • Eberhart Teuscher, Matthias F. Melzig, Ulrike Lindequist: Biogenic Medicines , ISBN 3-8047-2073-0 .

Web links

Individual evidence

  1. ^ Entry on ergot alkaloids in the Lexicon of Nutrition , Wissenschaft-Online-Lexika, accessed on November 9, 2011.
  2. ↑ a b c d Entry on Ergot alkaloids. In: Römpp Online . Georg Thieme Verlag, accessed on November 9, 2011.
  3. ↑ a b Entry on ergot in the Lexicon of Medicinal Plants and Drugs , Wissenschaft-Online-Lexika, accessed on November 10, 2011.
  4. ↑ Christopher L. Schardl, Daniel G. Panaccione and Paul Tudzynski: ERGOT ALKALOIDS - BIOLOGY AND MOLECULAR BIOLOGY . In: Geoffrey A. Cordell (Ed.): THE ALKALOIDS . 1st edition. tape 63 . Academic Press / Elsevier, Amsterdam, Boston, Heidelberg, London, Oxford, Paris, San Diego, San Francisco, Singapore, Sidney, Tokyo 2006, ISBN 978-0-12-469563-4 , chap. 2 , p. 45-86 .
  5. ↑ Debra E. Frederickson, Peter G. Mantle: Claviceps africana sp. nov .; the distinctive ergot pathogen of sorghum in Africa . In: Mycol. Res . 93, No. 9, August, pp. 1101-1107.
  6. ↑ M. Isaka, P. Kittakoop, Y. Thebtaranonth: Secondary Metabolites of Clavicipitalean Fungi . In: James Francis White (ed.): Clavicipitalean fungi: evolutionary biology, chemistry, biocontrol, and cultural impacts . CRC Press, 2003, ISBN 0824742559 , pp. 25-56.
  7. ↑ Klaus B. Tenberge: Biology and Life Strategy of the ergot fungi . In: Vladimír Křen, Ladislav Cvak (eds.): Ergot: the genus Claviceps . CRC Press, 1999, ISBN 9789057023750 , pp. 411-440.
  8. ↑ Eckart Eich: Tryptophan-derived alkaloid . In: Solanaceae and convolvulaceae - secondary metabolites: biosynthesis, chemotaxonomy, biological and economic significance . Springer, 2008, ISBN 3540745408 , pp. 213-260.
  9. ↑ Steiner U, Leibner S, Schardl CL, Leuchtmann A, Leistner E: Periglandula, a new fungal genus within the Clavicipitaceae and its association with Convolvulaceae . In: Mycologia . 103, No. 5, 2011, pp. 1133-1145. doi : 10.3852 / 11-031 . PMID 21558502 .
  10. ↑ Anatoly G. Kozlovsky: Producers of ergot alkaloids out of the Claviceps genus . In: Vladimir Kren, Ladislav Cvak (eds.): Ergot: The Genus Claviceps. Medicinal and Aromatic Plants - Industrial Profiles . CRC Press, 2004, ISBN 0203304195 , pp. 479-499.