Chemical structure of ergoline

Ergoline is a chemical compound whose structure serves as the skeleton for a diverse range of alkaloids and synthetic drugs. Substances derived from ergoline are used clinically as oxytocics and in the treatment of migraine and Parkinson's disease, and are implicated in the disease ergotism and in the action of psychedelic drugs such as ololiuhqui and LSD.

Chemistry

There are three main classes of ergoline derivatives, the water-soluble amides of lysergic acid, the water-insoluble ergopeptide alkaloids, and the clavine group.

Lysergic acid amides

The prototype of this class is

• Ergine (d-lysergic acid amide, LSA, LAA, LA-111)
  • IUPAC name: 9,10-didehydro-6-methylergoline-8beta-carboxamide
  • CAS number: 478-94-4

Other important members include:

• 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: lysergamide
  • IUPAC name: (8beta)-9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-carboxamide
  • CAS number: 50-37-3

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

Peptide alkaloids

These compounds have a tripeptide structure attached to the basic ergoline ring, in the same location as the amide group of the lysergic acid derivatives. Some of the important ergopeptides are summarized below. In addition to the following ergopeptides, a commonly encountered term is ergotoxine, which refers to a mixture of equal proportions of ergocristine, ergocornine and ergocryptine.

• Ergotamine
  • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-, (5'-alpha)- (9CI)
  • CAS number: 113-15-5
• 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
• Ergocryptine
  • IUPAC name:Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, (5'alpha)- (9CI)
  • CAS number: 511-09-1
• Bromocriptine (INN)
  • IUPAC name: Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, (5'alpha)-
  • CAS number: 25614-03-3
• Ergovaline
  • IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylethyl)-, (5'alpha)-
  • CAS number: 2873-38-3

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.

Others

Some synthetic ergoline derivatives do fall easily into any of the above groups. Some examples are:

• Pergolide (INN)
  • IUPAC name: (8beta)-8-((methylthio)methyl)-6-propyl-ergoline
  • CAS number: 66104-22-1
• Lisuride (INN)
  • IUPAC name: 3-(9,10-didehydro-6-methylergolin-8alpha-yl)-1,1-diethylurea
  • CAS number: 18016-80-3

History & Uses

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 1907 with the isolation by G. Barger and F. H. Carrin 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 A. 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. In addition to the naturally occurring ergonovine (used as an oxytocic) and ergotamine (an analgesic used to control migraine), synthetic derivatives of continuing importance today are the oxytocic methergine, the anti-migraine drugs dihydroergotamine and methysergide, the anti-senility nootropic (smart drug) 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 of all is the psychedelic drug LSD.

In 1960, Albert Hoffman (discoverer of methergine, dihydroergotamine, Hydergine and LSD) delivered a speech that was to cause shockwaves of incredulity and even disbelief in the scientific community. Ergoline alkaloids, previously only known from the lower fungi, had been found in two species of flowering plants. These were 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". Hoffman's result was later confirmed by other studies. 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 was later found to include similar alkaloids. It is possible, though not proven, that ergine and/or isoergine are responsible for the hallucinogenic effects.

See Also

• Ergot
• LSD
• Ergine
• Migraine
• Albert Hoffman

External Links

• The Ergot Alkaloids (A. T. Sneden) (http://www.people.vcu.edu/~asneden/The%20Ergot%20Alkaloids.pdf)
• The Ergot Alkaloids Story (Z. Madlom) (http://www.world-of-fungi.org/Mostly_Medical/Ziad_Madlom/Ergot_alkaloids.htm)
• The Psychoactive Ergot Alkaloids and their occurrence in the Microfungi -- M. P. Bock and D. G. Parbery (http://www.tacethno.com/info/claviceps/ergotalkfungi.txt)
• The Discovery of LSD and Subsequent Investigations on Naturally Occurring Hallucinogens (A. Hoffman) (http://www.psychedelic-library.org/hofmann.htm)
• Hoffman, A. Teonanácatl and Ololiuqui, two ancient magic drugs of Mexico Bulletin on Narcotics 1971 1 3 (http://www.erowid.org/plants/mushrooms/references/other/1971_hofmann_bulletin-narcotics.shtml)
• LSD, My Problem Child (A. Hoffman) (http://www.psychedelic-library.org/child.htm)
• TiHKAL (A & A Shulgin) #26 (http://www.erowid.org/library/books_online/tihkal/tihkal26.shtml)