UNIVERSIDAD DEL QUINDÍO

FACULTAD DE CIENCIAS BÁSICAS Y TECNOLOGÍAS

PROGRAMA DE QUÍMICA Prof. Fernando Agudelo A.
FITOQUÍMICA II

ALCALOIDES DERIVADOS
DEL AMINOÁCIDO TRIPTÓFANO
Indole alkaloids are derived from the amino acid tryptophan as can easily be
discerned by comparing their nitrogen containing nucleus to the chemical structure of
tryptophan.
COOH

NH2
N N
H H
Triptófano Núcleo de Indol
 Reserpina: alcaloide antihipertensivo que ya no
se emplea en clínica humana

N
H3CO N

OCH3

H3CO C OC OCH3
O OCH3 O
OCH3
 MOLÉCULAS QUE PRESENTAN EL NUCLEO DE INDOL

Serotonina: molécula encontrada en el cerebro y Melatonina: molécula con actividad

relacionada con procesos mentales antioxidante H
HO NH2 H3CO N CH3

N O
N
H H

L.S.D: alucinógeno sintético

Indigo: tinte de amplia utilidad O
HC
3
O H CH3
N N
N
H3C
N
H O
N
H
Important classes of indole alkaloids include:
the ergot alkaloids (ergotamine, ergocristine, etc.),
the fescue alkaloids (ergovaline, ergosine, ergonine, lysergic acid amide),
3-methylindole (produced by rumen fermentation of tryptophan), and
the beta-carbolines.
CLASIFICACIÓN

-TRIPTAMINAS
-Simples: β-carbolinas e indoleninas
-Complejas (isoprénicas o no isoprénicas)

-NO TRIPTAMINAS

-ALCALOIDES DERIVADOS DE TRIPTAMINA Y β-CARBOLINAS

Triptamina Harmano
NH2

N
N N
H H
β-Carboline (9H-pyrido[3,4-b]indole) is an organic amine that is the prototype of a class of
compounds known as β-carbolines.

β-carboline alkaloids are widespread in plants and animals, and frequently act as monoamine
oxidase inhibitors (MAOI). As components of the liana Banisteriopsis caapi, the β-carbolines
harmine, harmaline, and tetrahydroharmine play a pivotal role in the pharmacology of the
psychedelic brew ayahuasca. Some β-carbolines, notably tryptoline and pinoline, are formed
naturally in the human body. The latter is implicated along with melatonin in the role of the
pineal gland in regulating the sleep-wake cycle.[citation needed] The β-carboline can link to cerebral
benzodiazepine receptors and induce inverse agonist effect.

United States Patent Number 5591738 describes a method for treating various chemical
dependencies via the administration of beta-carbolines.[1]

Structure

The structure of β-carboline is similar to that of tryptamine, with the ethylamine chain re-
connected to the indole ring via an extra carbon atom, to produce a three-ringed structure.
Indeed, biosynthesis of β-carbolines is believed to follow this route from analogous
tryptamines. Different levels of saturation are possible in the third ring, which is indicated
here in the structural formula by colouring the optionally double bonds red and blue:

"There are presently 64 known .beta.-carboline alkaloids dispersed throughout at least eight
plant families."[1] The seeds of Peganum harmala (Syrian Rue) are a good source of beta-
carbolines, since they contain about 2-6% alkaloids, most of which is harmaline.[2][unreliable source?]

As a result of the presence of Beta-carbolines in the cuticle of Scorpions, they are known to
glow when exposed to certain wavelengths of ultraviolet light such as that produced by a
blacklight.[3]

Harmala
The MAOI (Monoamine oxidase inhibitor) alkaloids found in seeds of Peganum harmala
(also known as Harmal or Syrian Rue)- harmine, harmaline, and tetrahydroharmine- are
collectively known as harmala alkaloids. The harmala alkaloids are of great interest for their
complicated relation to phyto-indole entheogens used in Amazonian shamanism. The harmala
alkaloid harmine - once known as Telepathine and Banisterine - is a naturally occurring
beta-carboline alkaloid that is structurally related to harmaline. The Shulgins suggest
harmaline is a breakdown product of harmine [1]. Harmine and harmaline are reversible
MAOIs. They can stimulate the central nervous system by inhibiting the metabolism of
monoamine compounds such as serotonin.

The harmala alkaloids occur in harmal in concentrations of roughly 3%, though tests have
documented anywhere from 2-7%, as natural sources tend to vary widely in chemical makeup.
Harmala alkaloids are also found in the Banisteriopsis caapi vine, the key plant ingredient in
the sacramental beverage Ayahuasca, in concentrations that range between 0.31-8.43% for
harmine, 0.03-0.83% for harmaline and 0.05-2.94% for tetrahydroharmine [THH].[1] Many
other psychoactive plants are often added to Ayahuasca to achieve visionary consciousness,
including leaves from Psychotria viridis, a source of DMT, The harmala alkaloids serve to
potentiate these brewed compounds by preventing their breakdown in the digestive tract. The
harmala alkaloids are also psychoactive on their own if the dosage is sufficient, perhaps due
to endogenous sources of DMT in the human brain.

Harmala alkaloids are also found in many other plants, such as tobacco and passion flower.

Telepathine was originally thought to be the active chemical constituent of Banisteriopsis

caapi, a key plant ingredient in the preparation of Ayahuasca; a sacramental beverage from
the Amazon. This isolated chemical was so named because of the reported effects of
Ayahuasca among the indigenous users, including: collective contact with and/or visions of
jaguars, snakes, and jeweled birds, and ancestral spirits; the ability to see future events; and as
the name suggests, telepathic communication among tribal members. It was assumed to be a
newly discovered chemical at the time, however, it was soon realized that Telepathine was
already more widely known as "harmine" from its previous discovery in Peganum harmala
(Syrian Rue).
Uses

As mentioned above, some harmala alkaloids can be used as an MAOI (MonoAmine Oxidase
Inhibitor) to facilitate the ingestion of DMT and other tryptamines; while not generally used
as a hallucinogen alone, there are reports of such use. [2] In high doses, it acts as purgative.
Harmala alkaloids from Banisteriopsis caapi have been used to treat Parkinson's disease.
Additionally, harmaline is used as a model for Essential Tremor (ET) when injected to
animals. Rats being treated with harmaline exhibit severe tremors after 5-7 minutes.

It is important to note that unlike synthetic pharmaceutical MAOIs such as phenelzine,

harmine is reversible and selective meaning it does not have nearly as high a risk for the
"cheese syndrome" caused by consuming tyramine-containing foods, which is a risk
associated with monoamine oxidase A inhibitors, but not monoamine oxidase B inhibitors.[3]

Anticancer

"Harmine showed cytotoxicity against HL60 and K562 cell lines. This could explain the
cytotoxic effect of P. harmala on these cells."[4]
AYAHUASCA: VISIONARY VINE OF THE AMAZON

Banisteriopsis caapi (Malpighiaceae)

Ayahuasca, caapi, kahpi, mihi, dapa, and yage are all terms used in reference to the
hallucinogenic drink made from the bark of the neotropical lowland rainforest lianas,
Banisteriopsis caapi and B. inebrians. The drink was originally used by the indigenous
people of the upper Amazon and Orinoco rivers and is prepared by boiling the bark in water.
The hallucinogens present belong to the beta-carboline class of alkaloids and the major
psychoactive ingredients are harmaline, and to a lesser extent, harmine and tetrahydro
harmine. In addition to the hallucinogenic effects of the beta-carbolines, Psychotria viridis
or Diplopterys cabrerana , are often added. Both these plants contain dimethyl tryptamine
(DMT) and it seems that the effects of DMT are strongly potentiated by the mono amine
oxidase inhibiting beta-carbolines.
Current research on the pharmacological effects of beta-carbolines and ayahuasca are being
undertaken by research groups at the University of California at Los Angeles as part of the
Hoasca Project
There is also a growing body of evidence that points to the use of isoquinoline and
tryptamine-related alkaloids such as the beta-carbolines as a strategy for the control of
intestinal helminths and other microbes by forest dwelling people. It is readily accepted that
hallucinogen use by the indigenous people of tropical America has a long history and is an
integral part of their culture. In addition, during native ceremonies, repeated references are
made to the cleansing and purifying properties of these drugs. Because these compounds are
not only hallucinogens, but powerful emetics with antimicrobial and antihelminthic
properties, [5-6] it is suspected that the use of ayahuasca is more than vision seeking--it is
actually chemotherapy. The mode of this antihelminthic action is believed to be related to the
similarity in structure of serotonin to the beta-carboline alkaloids. It is possible that these
indole alkaloids are antagonists of serotonin in intestinal worm metabolism but little
comparative data on the effects of naturally occurring psychoactive drugs on parasitic worms
is available. Work in this area is currently underway.

NEUROPHARMACOLOGY of BETA-CARBOLINE ALKALOIDS

Beta-carbolines are a class of indole alkaloids which are structurally similar and
biosynthetically derived from the amino acid L-tryptophan. Trypophan derivatives are very
important in Central Nervous System (CNS) function and include the neurotransmitter,
serotonin, the Pineal metabolite, melatonin, the potent hallucinogen, dimethyl tryptamine
(DMT); and the mono amine oxidase inhibitors (MAOI), the beta-carbolines.
A clue as to the beta-carboline's mode of action can be seen by examining their relationship
to serotonin. It seems that ingestion of beta-carbolines raises serotonin levels and this
increase is a result of the inhibited action of mono amine oxidase (MAO). Normally, MAO
degrades the neurotransmitters serotonin, dopamine, and epinepherine. Therefore, inhibition
of this enzyme seriously affects brain chemistry.
MAO inhibitors fall into two classes: Irreversible and reversible MAOIs. In addition they can
inhibit either or both of the two types of the MAO enzyme, MAO-A and MAO-B which are
associated with serotonergic and dopaminergic neurons respectively [8] . Irreversible MAOIs
(e.g. the hydrazides iproniazid and phenelzine) bind permanently to the enzyme and cause
MAO inhibition lasting 1-2 weeks after ingestion. They are used clinically to treat depression.
Reversible MAOIs, such as moclobemide, which is used as an antidepressant, and the beta-
carbolines harmine and harmaline, are effective for a much shorter time, usually less than
twenty-four hours. There are significant dangers in using MAO inhibitors. Most MAOIs
potentiate the cardiovascular effects of tyramine and other monoamines found in foods. There
are therefore several foods that should be avoided when on MAOIs. Ingestion of aged cheese,
beer, wine, pickled herring, chicken liver, yeast, large amounts of coffee, citrus fruits, canned
figs, broad beans, chocolate or cream while MAO is inhibited can cause a hypertensive crisis
including a dangerous rise in blood pressure. Effects of amphetamines, general anaesthetics,
sedatives, anti-histamines, alcohol, potent analgesics and anticholinergic and antidepressant
agents are prolonged and intensified. Overdosage of MAOIs by themselves is also possible
with effects including hyperreflexia and convulsions[8].
Another result of ingesting beta-carbolines or other MAOIs at high doses is the occurrence
of vivid visual hallucinations. It is not understood whether this hallucinatory effect is related
directly to the inhibition of MAO, but due to the structural similarity to serotonin, it is
possible that beta-carbolines are acting as serotonin antagonists in much the same way
LSD does. The current theory implicates LSD temporarily binding to the serotonin receptor.
Upon the release of LSD an over abundance of serotonin is present in the CNS and affects
perception. It is notable, however, that the hallucinations experienced from ingestion of beta-
carbolines differ from those experienced with LSD.
BETA-CARBOLINE CONTAINING PLANTS
Images property of www.nepenthes.com

The beta-carbolines are distributed among 23 angiosperm plant families. The most
commonly used trivial nomenclature of the beta-carboline alkaloids is based on the root
"harm" from Peganum harmala the plant that was first known to contain these compounds.
Peganum harmala (Zygophyllaceae) is a weed and wasteland species native to the deserts
of India whose range stretches through the Gobi desert into the former Soviet Union. The
mature Peganum harmala or the Syrian rue is a common livestock poison in the former
Soviet rangelands but specific informtion concerning the extent of its damage are difficult to
locate. The content of beta-carbolines in the Syrian rue range from 2% to 4%.
mature Peganum harmala
Peganum harmala habitat
Peganum harmala drawing
Passiflora incarnata (Passifloraceae) or the Maypop passion flower is a common ornamental
in the United States. This species and other varieties have been used as model systems to
investigate the effects beta-carboline alkaloids have on insect feeding patterns [7]. The
amount of beta-carbolines in this species range from 0.5 -1.0%.
MaturePassiflora incarnata
Passiflora incarnata seedling
Banisteriopsis caapi (Malpighiaceae) is a liana native to the new world tropics where it is
the principle ingredient in the hallucinogenic beverage ayauasca. This plant and the
beverage have recieved attention lately by several members of the scientific community
involved with the Hoasca Project and more underground information can be found by
referencing the King of Brews. The beta-carboline content in Banisteriopsis caapi ranges
from 1.0 - 2.0%.
Peganum harmala
Matture Passiflora incarnata

Bannisteropsis caapi

Angiosperm Families Containing Beta-Carbolines

Apocynaceae Elaeagnaceae
Amsonia tabernaemontana Elaegnus angustifolia
Apocynum cannabinum E. commutata
Apidosperma exalatum E. hortensis
A. polyneuron E. orientalis
Ochrosia nakainana E. spinosa
Pleicarpa mutica Hippophae rhamnoides
Shepherdia argentea
S. canadensis
Bignoniaceae Fabaceae
Newbouldia laevis Acacia baileyana
Calycanthaceae A. complanata
Calycanthus occidentalis A. simplicifolia
Chenopodiaceae Anadenanthera peregrim
Hammada leptoclada Burkea africana
Kochia scoparia Desmodium gangeticum
Combretaceae D. gyrans
Guiera senegalensis S. pulchellum
Cyperaceae Mucuna pruriens
Carex brevicollis Petalostylis labicheoides
C. parva Prosopis nigra
Gramineae Lauraceae
Arundo donax Nectandra megapotamica
Festuca arundinacea Loganiaceae
Lolium perenne Strychnos melinoniana
Phalaris aquatica S. usambarensis
P. arundinacea

Malpighiaceae Rutaceae
Banisteriopsis argentea Araliopsis tabouensis
B. caapi Findersia laevicarpa
B. inebrians Xanthoxylum rhetsa
B. lutea
B. rusbyana
Cabi pratensis
Myristicaceae Passifloraceae
Gymnacranthera paniculata Passiflora actinea
Virola cuspidata P. alata
V. rufula P. alba
V. theidora P. bryonioides
Ochnaceae P. capsularis
Testulea gabonensis P. caerulea
Palmae P. decaisneana
Plectocomiopsis geminiflorus P. edulis
Papaveraceae P. eichleriana
Meconopsis horridula P. foetida
M. napaulensis P. incarnata
M. robusta P. quadrangularis
M. rudis P. ruberosa
M. panuculata P. subpeltata
Papaver rhoeas P. warmingii
Polygonaceae Solanaceae
Calligonum minimum Vestia lycioides
Symplocaceae
Symplocos racemosa
Rubiaceae Simaroubaceae
Borreria verticillata Ailanthus malabarica
Leptactinia densiflora Perriera madagascariensis
Nauclea diderrichii Picrasma ailanthoides
Ophiorrhiza japonica P. crenata
Pauridiantha callicarpoides P. excelsa
P. dewevrei P. javanica
P. lyalli
P. viridiflora Tiliaceae
Pavetta lanceolata Grewia mollis
Psychotria carthaginesis Zygophyllaceae
P. viridis Fagonia cretica
Simira klugii Nitraria schoberi
S. rubra Perganum harmala
Uncaria attenuata Tribulus terrestris
U. canescens Zygophyllum fabago
U. orientalis
Sapotaceae
Chrysophyllum lacourtianum

MIND BENDING BETA-CARBOLINE REFERENCES

[1] Allen, J.R. and B.R. Holmstedt. (1979). Phytochemistry (19) 1573-1582.
[2] Poindexter, E. H., and R.D. Carpenter (1962). Phytochemistry (1) 215
[3] Kettenes-van Den Bouch, J.J. and C.A. Salemink. (1977). J. Chromatography. (131) 422.
[4] Proliac, A. and M. Blanc. (1976). Helv. Chem. Acta. (59) 2503
[5] Rodriguez, E. and J.C. Cavin. (1982). Journal of Ethnopharmacology (6) 303-309.
[6] Mckenna, D. and G.H.N. Towers. (1981). Phytochemistry 20(5) 1001-1004
[7] Cavin J.C. and E. Rodriguez. (1980) Journal of Chemical Ecology (14) 475-484
[8] Cooper, J.R. Bloom, F.E. and R.H. Roth (1991) Biochemical Basis of
Neuropharmacology 338-380
Agaricaceas alucinógenas de América del Sur.

Psilocibina
Psilocina
OH CH3 OPO3H2 CH3
N N
CH3 CH3

N N
H H
(América del Sur)

Psilocybin (pronounced [saɪləˈsaɪbɪn], sye-lə-SYE-bin) (also known as psilocybine) is a

psychedelic indole of the tryptamine family, found in psilocybin mushrooms. It is present in
hundreds of species of fungi, including those of the genus Psilocybe, such as Psilocybe
cubensis and Psilocybe semilanceata, but also reportedly isolated from a dozen or so other
genera. Psilocybin mushrooms are commonly called "magic mushrooms" or more simply
"shrooms". Possession, and in some cases usage, of psilocybin or psilocin has been outlawed
in most countries across the globe.[1] Proponents of its usage consider it to be an entheogen
and a tool to supplement various types of practices for transcendence, including in meditation,
psychonautics, and psychedelic psychotherapy. The intensity and duration of entheogenic
effects of psilocybin mushrooms are highly variable, depending on species/cultivar of
mushrooms, dosage, individual physiology, and set and setting. Though psilocybin rarely
attracts much attention from mainstream media, when it does the focus tends to be on the
recreational use, generally excluding any other uses of the drug.

Chemistry
Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) is a prodrug that is converted
into the pharmacologically active compound psilocin in the body by dephosphorylation.[2]
This chemical reaction takes place under strongly acidic conditions or enzymatically by
phosphatases in the body. Psilocybin is a zwitterionic alkaloid that is soluble in water,
moderately soluble in methanol and ethanol, and insoluble in most organic solvents.

Albert Hofmann, the well-known chemist who discovered and experimented with LSD, was
the first to recognize the importance and chemical structure of the pure compounds psilocybin
and psilocin. Hofmann was aided in this process by his willingness to ingest extracts isolated
from Psilocybe. Hofmann's colleagues at the University of Delaware were also trying to
isolate the active principle, but were unsuccessful.[3]

Biology
Psilocybin is a naturally-occurring compound found in varying concentrations in some species
of the genera of Psilocybe spp. and Panaeolus spp. (fungal Phylum Basidiomycota). The
spores of these mushrooms are completely free of both psilocybin and psilocin. Mushroom
caps tend to contain more of the psychoactive compounds than the stems.[4][5][6] The total
potency varies greatly between species and even between specimens of one species in the
same batch.[7] Younger, smaller mushrooms are relatively higher in alkaloids and have a
milder taste than larger, mature mushrooms. Mature mycelium contains some psilocybin,
while young mycelium (recently germinated from spores) does not contain appreciable
amounts of alkaloids.[8] Many species of mushrooms containing psilocybin also contain small
amounts of the psilocybin analogs baeocystin and norbaeocystin.[9][10][11] Most species of
psilocybin-containing mushrooms bruise blue when handled or damaged[12] due to the
oxidization of phenolic compounds. This is not a definitive method of identification or
determining a mushroom's potency.

Pharmacology
Psilocybin is rapidly dephosphorylated in the body to psilocin which then acts as a partial
agonist at the 5-HT2A serotonin receptor in the brain where it mimics the effects of serotonin
(5-HT). Psilocin is an 5-HT1A and 5-HT2A/2C agonist.[13]

Medicine
Psilocybin has no recognized medical uses. However, it has been investigated as an
experimental treatment for several disorders.

In 1961, Timothy Leary and Richard Alpert ran the Harvard Psilocybin Project, carrying out a
number of experiments concerning the use of psilocybin in the treatment of personality
disorders and other uses in psychological counselling.

A pilot study led by Francisco Moreno and supported by Multidisciplinary Association for
Psychedelic Studies (MAPS) studied the effects of psilocybin on nine patients with obsessive-
compulsive disorder.[14] The study found that psilocybin could be safely given to patients with
OCD but, due to the study design, it was unable to confirm or deny that psilocybin was
effective in relieving obsessive compulsive disorder symptoms.[15]

Two current studies are investigating the possibility that psilocybin can ease the psychological
suffering associated with cancer. One study, led by Charles Grob, involves 12 subjects with
terminal cancer being administered the hallucinogen or a placebo in two separate sessions. [16]
[17][18]
A second study, led by Roland Griffiths at Johns Hopkins, will administer psilocybin on
two occasions to people "with a current or past diagnosis of cancer who have some anxiety or
are feeling down about their cancer".[19]
Toxicity
The toxicity of psilocybin is relatively low; in rats, the oral LD50 is 280mg/kg, approximately
one and a half times that of caffeine. When administered intravenously in rabbits, psilocybin's
LD50 is approximately 12.5mg/kg[20] (however rabbits are extremely intolerant to the effects of
most psychoactive drugs). The lethal dose from psilocybin toxicity alone is unknown at
recreational or medicinal levels, and has never been documented. Psilocybin makes up
roughly 1% of the weight of Psilocybe cubensis mushrooms, and so nearly 1.7 kilograms of
dried mushrooms, or 17 kilograms of fresh mushrooms, would be required for a 60kg person
to reach the 280mg/kg LD50 rate of rats.
 Miristicaceas (Virola calophylloidea Markgraf)
Leguminosas (Anadenanthera peregrina)
Malpigiaceas (Banisteriopsis caapi)
N,N-dimetiltriptamina, 5-Metoxi-N,N-dimetiltriptamina

N,N-dimetiltriptamina 5-Metoxi-N,N-dimetiltriptamina
CH3 CH3
N H3CO N
CH3 CH3

N N
H H

OTRA CLASIFICACIÓN

- ALCALOIDES DEL ESERÉ

Leguminosas
Haba del Calabar (Physostigma venenosum Balf)
 Eserina

O O

NH
N N
H
CH3 CH3

Geneserina

H3C
O O

NH N
H3C N O CH3
H
H
- ALCALOIDES DERIVADOS DE LA ERGOLINA.
LSD
 ALCALOIDES DEL ERGOT

Ergolina

N
H

Hongo Claviceps purpurea

Envenenamiento en Europa (Edad Media) por consumo de pan hecho de centeno
infectado por C. purpurea.

Síntomas.
Francia: gangrena generalizada (debido a las propiedades vasoconstrictoras
de algunos alcaloides)
Rusia: convulsiones y profunda perturbación mental (se arrojaban desde los
pisos altos de los edificios).

La afección se conoció como “Fuego de San Antonio” debido a la afección de

tipo convulsivo.

El Acido Lisérgico y la Agroclavina han sido estudiados extensamente.

Ergoline is a chemical compound whose structural skeleton is contained in a diverse range of

alkaloids and a few psychedelic drugs (ololiuhqui, LSD). Ergoline derivatives are used
clinically for the purpose of vasoconstriction (5-HT1 receptor agonists - ergotamine) and in
the treatment of migraine (used with caffeine) and Parkinson's disease, some are implicated in
the disease ergotism. Ergometrine and ergotamine are listed as Table I precursors under the
United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic
Substances.[1]
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.[2]

Lysergic acid amides

Lysergamides
 Ergine (LSA, D-lysergic acid amide, LAA, LA-111)
o IUPAC name: 9,10-didehydro-6-methylergoline-8beta-carboxamide
o CAS number: 478-94-4
 Ergonovine (ergobasine)
o INN: ergometrine
o IUPAC name: (8beta(S))−9,10-didehydro-N-(2-hydroxy-1-methylethyl)−6-
methyl-ergoline-8-carboxamide
o CAS number: 60-79-7
 Methergine (ME-277)
o INN: methylergometrine
o IUPAC name: (8beta(S))−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−6-
methyl-ergoline-8-carboxamide
o CAS number: 113-42-8
 Methysergide (UML-491)
o INN: methysergide
o IUPAC name: (8beta)−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−1,6-
dimethyl-ergoline-8-carboxamide
o CAS number: 361-37-5
 LSD (D-lysergic acid diethylamide, LSD-25)
o INN: lysergide
o IUPAC name: (8beta)−9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-
carboxamide
o 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. This tripeptide moiety contains an
unusual cyclol bond >N-C(OH)< at the juncture between the two lactam rings. Some of the
important ergopeptines (also known as ergopeptides) are summarized below. 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.

 Ergotamine
o IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-
(phenylmethyl)-, (5'-alpha)- (9CI)
o CAS number: 113-15-5
 Ergocristine
o IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-
(phenylmethyl)-, (5'-alpha)-
o CAS number: 511-08-0
 Ergocornine
o IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2',5'-bis(1-
methylethyl)-, (5'-alpha)-
o CAS number: 564-36-3
 Ergocryptine
o IUPAC name:Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(2-
methylpropyl)-, (5'alpha)- (9CI)
o CAS number: 511-09-1
 Bromocriptine (INN)
o IUPAC name: Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-
methylethyl)−5'-(2-methylpropyl)-, (5'alpha)-
o CAS number: 25614-03-3
 Ergovaline
o IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-
methylethyl)-, (5'alpha)-
o CAS number: 2873-38-3
 Triptófano + Mevalonato marcado: incorporados

H2N CO2H H2N CO2H

( IPP ) +

OPP N N
DMAPP H H

HOOC C 1 (SAM)
NHMe
H HOOC
H2N R

N
H N
Chanoclavina I H

O
H
NHMe NMe NMe
H H H

N N N
H H H
Agroclavina
 HOOC
NMe

N
H
Ácido lisérgico

O
Et C
N NMe
Et

Laboratorio

N
H
L.S.D. útil en siquiatría
Alucinógeno potente

O
O
N NMe
2-Bromoergocriptina N N H
O
Parlodel (R)
O
Inhibidor de prolactina
Br

N
H
 ERGOMETRINA Y ERGOTAMINA
Importancia medicinal, uterocontractoras.
Ayudan al parto (Usadas desde la edad media como
extractos crudos de C. purpurea)

Revisar ergometrina y ergonovina

CH3 O

HOCH2 N NMe
H

Ergometrina

N
H

OH
O
N O

O N N NMe
H O H

Ergotamina

N
H

Ocurrencia de los Alcaloides del Ergot en Plantas Superiores

El Ololiuqui es una droga alucinógena usada en ceremonias religiosas por los
nativos de diversos países de Centroamérica. La droga es obtenida de las semillas
de dos plantas, Ipomoea violacea L, y Rivea corymbosa (L.) Hall; ambas de la
familia Convolvulaceae. En la I. violacea se encuentra el ácido de la Chanoclavina-
I.
 HOOC
NMe
H
Ácido chanoclavina I H

N
H

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 not fall easily into any of the above groups. Some
examples are:

 Pergolide (INN)
o IUPAC name: (8beta)−8-((methylthio)methyl)−6-propyl-ergoline
o CAS number: 66104-22-1
 Lisuride (INN)
o IUPAC name: 3-(9,10-didehydro-6-methylergolin-8alpha-yl)−1,1-diethylurea
o 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 (a vasoconstrictor used
to control migraine), synthetic derivatives of continuing importance today 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 of all is the psychedelic drug LSD.
In 1960, Albert Hofmann (discoverer of methergine, dihydroergotamine, Hydergine and
lysergic acid diethylamide) delivered a speech that was to cause shockwaves of incredulity
and 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"[verification needed][citation needed]. Hofmann'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 or isoergine are responsible for the hallucinogenic effects.
However, while Hofmann's discovery is an important landmark in the research of ergot
alkaloids, a recent study has provided evidence for 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.[3]

Ergot refers to a group of fungi of the genus Claviceps (ergot fungi).[1] The most prominent
member of this group is Claviceps purpurea. This fungus grows on rye and related plants, and
can cause ergotism in humans and other mammals consuming seeds contaminated with the
fruiting structure of this fungus, called an ergot sclerotium. [2][3] There are about 50 known
species of Claviceps, most of them in the tropical regions. Economically important species are
C. purpurea (parasitic on grasses and cereals), C. fusiformis (on pearl millet, buffel grass), C.
paspali (on dallis grass), and C. africana[4](on sorghum). C. purpurea most commonly affects
outcrossing species such as rye (its most common host), as well as triticale, wheat and barley.
It affects oats only rarely.

There are at least three races or varieties of C. purpurea, differing in their host specificity:[5]

 G1 — land grasses of open meadows and fields;

 G2 — grasses from moist, forest, and mountain habitats;
 G3 (C. purpurea var. spartinae) — salt marsh grasses (Spartina, Distichlis).
Ergina
LSA, also known as d-lysergic acid amide, d-lysergamide, ergine, and LA-111, is an
alkaloid of the ergoline family that occurs in various species of vines of the Convolvulaceae
and some species of fungi. As the dominant alkaloid in the hallucinogenic seeds of Rivea
corymbosa (ololiuhqui), Argyreia nervosa (Hawaiian baby woodrose) and Ipomoea tricolor
(morning glories, tlitliltzin), it is often stated that ergine and/or isoergine (its epimer) is
responsible for the psychedelic activity. In fact, the effects of synthetic LSA and iso-LSA are
not particularly psychedelic, see Mixing the Kykeon below for a summary of human trials, and
Chapter 17 and entry #26 of TiHKAL for further discussion. As a precursor to LSD, ergine is
a DEA schedule III drug in the United States.
Rivea corymbosa (common synonym: Turbina corymbosa), is a species of morning glory,
native throughout Latin America from Mexico in the North to Peru in the South and widely
naturalised elsewhere. It is a perennial climbing vine with white flowers, often planted as an
ornamental plant. This plant also occurs in Cuba, where it usually blooms from early
December to February. Its flowers secrete copious amount of nectar, and the honey the bees
make from it is very clear and aromatic. It is considered one of the main honey plants from
the island.

Known to natives of Mexico as Ololiúqui (also spelled ololiuhqui or ololiuqui), its seeds,
while little known outside of Mexico, were perhaps the most common hallucinogenic drug
used by the natives.

In 1941, Richard Evans Schultes first identified ololiuhqui as Rivea corymbosa and the
chemical composition was first described on August 18, 1960, in a paper by Dr. Albert
Hofmann. The seeds contain ergine (LSA), an ergoline alkaloid similar in structure to LSD.

The Nahuatl word ololiuhqui means "round thing", and refers to the small, brown, oval seeds
of the morning glory, not the plant itself, which is called coaxihuitl, "snake-plant", in Nahuatl,
and hiedra or bejuco in the Spanish language. The seeds, in Spanish, are sometimes called
semilla de la Virgen (seeds of the Virgin Mary).
The seeds are also used by Native curers in order to gain knowledge in curing practices and
ritual, as well as the causes for the illness.

This species is an invasive species to the United States. As well as to Australia, where it has
become more naturalized.

Ipomoea tricolor is a species of morning glory native to the New World tropics, and widely
cultivated and naturalised elsewhere. It is a herbaceous annual or perennial twining liana
growing to 2-4 m tall. The leaves are spirally arranged, 3-7 cm long with a 1.5-6 cm long
petiole. The flowers are trumpet-shaped, 4-9 cm diameter, most commonly blue with a white
to golden yellow centre.
A traditional use of morning glory seeds by Mexican Native Americans was first described by
Richard Schultes in 1941 in a short report documenting their use going back to Aztec times
(cited in TiHKAL by Alexander Shulgin). Further research was published in 1960, when Don
Thomes MacDougall reported that the seeds of Ipomoea tricolor were used as sacraments by
certain Zapotecs, sometimes in conjunction with the seeds of Rivea corymbosa, another
species which has a similar chemical composition, with lysergol instead of ergometrine.
Ergine was assayed for human activity by Albert Hofmann in self-trials in 1947, well before it
was known to be a natural compound. Intramuscular administration of a 500 microgram dose
led to a tired, dreamy state, with an inability to maintain clear thoughts. After a short period of
sleep the effects were gone, and normal baseline was recovered within five hours.[2] .
Natural occurrence

Ergine has been found in high concentrations of 20 µg/g dry weight in the grass Stipa robusta
(sleepygrass) infected with an Acremonium endophytic fungus together with other ergot
alkaloids [3].

It is also found in the seeds of several varieties of Morning Glories in concentrations of

approximately 1 µg per seed.

Ergotamine 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. It is used medicinally for
treatment of acute migraine attacks (sometimes in combination with caffeine), and to induce
childbirth and prevent post-partum haemorrhage. It was first isolated from the ergot fungus by
Arthur Stoll at Sandoz in 1918 and marketed as Gynergen in 1921. [1]

The mechanism of action of ergotamine is complex.[2] The molecule shares similarity with
neurotransmitters such as serotonin, dopamine, and adrenaline and can thus bind to several
cell receptors acting both as agonist and antagonist in signal transduction within cellular
tissues. The anti-migraine effect is due to constriction of the intercranial extracerebral blood
vessels through the 5-HT1B receptor, and by inhibiting trigeminal neurotransmission by 5-
HT1D receptors. Ergotamine also has effects on the dopamine and noradrenaline receptors. It is
its action on the D2 dopamine and 5-HT1A receptors that can cause some side effects. [3]

Biosynthesis

Ergotamine is a secondary metabolite (natural product) and the principal alkaloid produced by
the ergot fungus, Claviceps purpurea, and related fungi in the family Clavicipitaceae. Its
biosynthesis in these fungi requires the amino acid L-tryptophan and dimethylallyl
diphosphate. These precursor compounds are the substrates for the enzyme, dimethylallyl-
tryptophan (DMAT) synthase, catalyzing the first step in ergot alkaloid biosynthesis, i.e., the
prenylation of L-tryptophan. Further reactions, involving methyltransferase and oxygenase
enzymes, yield the ergoline, lysergic acid. Lysergic acid (LA) is the substrate of lysergyl
peptide synthetase, a nonribosomal peptide synthetase, which covalently links LA to the
amino acids, L-alanine, L-proline, and L-phenylalanine. Enzyme-catalyzed or spontaneous
cyclizations, oxygenations/oxidations, and isomerizations at selected residues precede, and
give rise to, formation of ergotamine.[4]

Drug uses

Ergotamine is also a precursor of LSD, lysergic acid diethylamide. It produces

vasoconstriction peripherally. It damages the peripheral epithelium and in high doses is
conducive to the creation of vascular stasis, thrombosis and gangrene. It can increase uterine
contractivity and occasionally is used therapeutically immediately post-partum to decrease
uterine bleeding. It continues to be prescribed for migraines. Contraindications include:
atherosclerosis, Buerger's syndrome, coronary artery disease, hepatic disease, pregnancy,
pruritus, Raynaud's syndrome, and renal disease. [5]
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 some plants. Amides of
lysergic acid, lysergamides, are widely used as pharmaceuticals and as psychedelic drugs
(LSD). Lysergic acid is usually produced by hydrolysis of lysergamides, but can also be
synthesized in the laboratory by a complex total synthesis. Lysergic acid monohydrate
crystallizes in very thin hexagonal leaflets when recrystallized from water. Lysergic acid
monohydrate, when dried (140 °C at 2 mmHg) forms anhydrous lysergic acid. Lysergic acid
is a chiral compound with two stereocenters. The isomer with inverted configuration at carbon
atom 8 close to the carboxy group is called isolysergic acid. Inversion at carbon 5 close to the
nitrogen atom leads to L-lysergic acid and L-isolysergic acid, respectively. Lysergic acid is
listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in
Narcotic Drugs and Psychotropic Substances.[1]